Application of teriparatide or salt thereof in preparation of osteoporosis treatment and / or prevention agent

Abstract

The present invention provides the use of teriparatide or a salt thereof in the preparation of a therapeutic and / or prophylactic agent for osteoporosis containing 28.2 [mu] g of teriparatide or a salt thereof such that the amount of teriparatide or a salt thereof is administered once at a frequency of two times per week.

Description

[0001] This application is a divisional application. The international application number of the original application is PCT / JP2019 / 030099, the international application date is July 31, 2019, the Chinese national application number is 201980004570.9, the date of entry into China is March 18, 2020, and the name of the invention is "A method for preventing or treating osteoporosis characterized by administering teriparatide or a salt thereof twice a week". Technical Field

[0002] The present invention relates to a method for preventing or treating osteoporosis, characterized in that teriparatide or a salt thereof is administered twice a week. Background Art

[0003] Osteoporosis is defined as "a skeletal disease characterized by a decrease in bone strength and an increased risk of fracture" (Non-Patent Document 1), and this definition is widely used.

[0004] The main purpose of osteoporosis prevention and treatment is to prevent or inhibit fractures, maintain life function and QOL (Quality of life), etc. Pain caused by fractures or reduction in body support function, followed by life function impairment due to motor dysfunction, are serious problems, so the clinical significance of prevention and treatment of osteoporosis, which is particularly high in risk of fractures, is very high.

[0005] Against this background, as drugs with the efficacy / effect of treating osteoporosis with a high risk of fracture, preparations for daily administration and preparations for once-weekly administration containing teriparatide or a salt thereof as an active ingredient have been developed, approved for sale, and are actually used in clinical settings (Non-Patent Documents 4 and 8).

[0006] However, preparations for daily administration and preparations for once-weekly administration containing teriparatide or a salt thereof as an active ingredient are not necessarily sufficiently excellent in terms of safety.

[0007] PTH is known to have a vascular smooth muscle relaxant effect (Non-patent Document 21). It has been reported that in a clinical trial using a preparation for daily administration, dizziness was significantly higher than in the placebo group (Non-patent Document 9). It is also known that in preparations for daily administration and once-a-week administration, shock, loss of consciousness accompanied by a temporary sharp drop in blood pressure, convulsions, and collapse may occur from just after administration to several hours later (Non-patent Documents 4, 8).

[0008] Alternatively, it has been reported that nausea, vomiting, headache, etc., are often experienced by administering teriparatide acetate (Non-Patent Document 9). For example, it has also been reported that in a clinical trial using a once-weekly dosing preparation, the frequency of nausea was significantly higher than that of the placebo group, and the value exceeded 20% of the entire once-weekly dosing preparation group, and the discontinuation rate due to adverse events also showed a value as high as about 20% (Non-Patent Document 5).

[0009] Furthermore, it has been reported that in a clinical trial using a preparation for continuous daily administration, the incidence of moderate hypercalcemia (greater than 10.6 mg / dl) was 11% (2% in the placebo group) (Non-Patent Document 7).

[0010] Furthermore, in trials using preparations for once-weekly administration or preparations for daily administration, fever was observed as an adverse event (Non-Patent Documents 6 and 21).

[0011] Generally, regarding the medication status in the drug treatment of osteoporosis, it is reported that 52.1% of patients have bone loss within 5 years after the start of treatment. In addition, the reduction in fracture suppression due to insufficient compliance with medication, the increase in the need to use rehabilitation facilities, and the stagnation of medical cost reduction are also considered problems (Non-patent Document 9). As factors related to poor compliance with medication, the presence of pain, side effects, and medication for gastrointestinal disorders can be exemplified (Non-patent Document 9).

[0012] On the other hand, regarding preparations containing teriparatide or its salt as an active ingredient, it has been pointed out that the treatment continuation rate is low, and it has been reported that the treatment continuation rate for 12 months is 34.9% (Non-patent Document 22). Regarding safety, it is known that there are concerns about reduced medication compliance due to side effects, and it has been reported that in a trial using a preparation for once-weekly administration, adverse events leading to non-serious discontinuation of the therapeutic drug were as high as 14.1% in the drug group (Non-patent Document 23).

[0013] As described above, preparations for daily administration and once-weekly administration containing teriparatide or a salt thereof as an active ingredient have many problems from the perspective of safety, and cannot necessarily be said to offer sufficient advantages from the perspective of effectiveness.

[0014] For example, it has been reported that in a clinical trial in which a preparation for administration once a week was provided to osteoporosis patients with a high risk of fracture and the administration period was 72 weeks, the lumbar vertebrae bone density increased by about 4.9 to 6.0% at 48 weeks after the start of administration (Patent Document 1 (Table 26), Non-Patent Document 5 (FIG.3)). In addition, it has been reported that in a clinical trial in which a preparation for administration once a week was provided to osteoporosis patients with a high risk of fracture and the administration period was 24 months, the lumbar vertebrae bone density increased by about 6.9% at 48 weeks after the start of administration (Non-Patent Document 6).

[0015] The effectiveness of the two drugs is known to be related to not only the bone density increasing effect but also the fracture suppressing effect. For example, a clinical trial using a preparation for daily administration has been reported to reduce the risk of vertebral fracture by 65% ​​(Non-Patent Document 7).

[0016] In addition, it is reported that in recent animal experiments and clinical studies, the daily administration of teriparatide has shown a strong bone formation promoting effect in parts with more spongy bones such as vertebral bodies, but on the other hand, it increases the space in cortical bones such as limb bones; and it is believed that in the intermittent administration of PTH, the effect on cortical bones may be different due to different administration frequencies; etc. (Non-patent Document 14). In addition, it is reported that CTX, one of the bone resorption markers, has confirmed a tendency to increase in a dose-dependent manner 24 weeks after the start of daily administration of teriparatide compared to the start of administration.

[0017] According to a study on ovariectomized rats, which are widely used as an osteoporosis model, it has been reported that bone density and bone strength increase in accordance with the dose of teriparatide administered per week (Non-Patent Document 14).

[0018] Prior art literature

[0019] Patent Literature

[0020] Patent Document 1: International Publication No. 2011 / 030774

[0021] Patent Document 2: Japanese Patent Application Laid-Open No. 8-73376

[0022] Patent Document 3: International Publication No. 2000 / 10596

[0023] Non-patent literature

[0024] Non-patent document 1: JAMA, (2001), Vol. 285, No. 6, pp. 785-795

[0025] Non-patent document 2: Osteoporos Int, (1999), Vol. 9, pp. 296-306

[0026] Non-patent document 3: J Bone Miner Metab (2004), Vol. 22, pp. 569-576

[0027] Non-patent document 4: Teribone (registered trademark) for subcutaneous injection 56.5 μg package insert (revised in August 2018)

[0028] Non-patent document 5: J Clin Endocrinol Metab (2012), Vol. 97, No. 9, pp. 3097-3106

[0029] Non-patent document 6: Adv Ther (2017), Vol. 34, pp. 1727-1740

[0030] Non-patent document 7: N Engl J Med (2001), Vol. 344, No. 19, pp. 1434-1441

[0031] Non-patent Document 8: Forteo (registered trademark) subcutaneous injection kit 600 μg package insert (revised in January 2018)

[0032] Non-patent literature 9: Guidelines for the prevention and treatment of osteoporosis (Guidelines for the prevention and treatment of osteoporosis) 2015 edition

[0033] Non-patent document 10: Diagnostic criteria for primary osteoporosis (Diagnostic criteria for primary osteoporosis) (revised in 2012)

[0034] Non-patent document 11: J Bone Miner Res (1993), Vol. 8, pp. 1137-1148

[0035] Non-patent document 12: Osteoporos Int (1995), Vol. 5, pp. 354-370

[0036] Non-patent document 13: J Bone Miner Metab (2004), Vol. 22, pp. 104-110

[0037] Non-patent document 14: Japanese Journal of Bone Morphology (2018), Vol. 28, pp. 31-37

[0038] Non-patent document 15: "Revised Guidelines for Clinical Evaluation Methods for Osteoporosis Drugs" (2017), No. 0707 No. 1 of the Clinical Evaluation Method for Osteoporosis Drugs

[0039] Non-patent document 16: Bone Vol.45 (2009), pp.1053-1058

[0040] Non-patent document 17: J Bone Miner Metab (2008), Vol. 26, pp. 624-634

[0041] Non-patent document 18: Kagoshima City Medical Journal (2006), Vol. 45, No. 9 “Regarding drug fever”

[0042] Non-patent document 19: JAPI (2008), Vol. 56, pp. 418-424

[0043] Non-patent document 20: Calcif Tissue Int (2014), Vol. 94, pp. 170-175

[0044] Non-patent document 21: Endocrine Reviews (1989), Vol. 10, No. 4, pp. 420-436

[0045] Non-patent literature 22: Arch Osteoporos. (2018), 13(1): 54, s11657-018-0466-0

[0046] Non-patent literature 23: Pharmaceutical Information Booklet (Drug Information Booklet) Japanese Standard Product Classification Number: 872439

[0047] Non-patent document 24: Journal of the Japanese Society of Internal Medicine (2012), Vol. 101, No. 4, pp. 1007-1014

[0048] Non-patent document 25: BoneKEy Rep (2014), 3, No. 512

[0049] Non-patent literature 26: Kawasaki Medical Association Journal (2010), 36(2), pp.153-157

[0050] Non-patent literature 27: PLOS ONE 12(4)e0175329 “Acute development of corticalporosity and endosteal bone formation from the daily but not weekly short-term administration of PTH in rabbit.” Summary of the invention

[0051] Problems to be solved by the invention

[0052] An object of the present invention is to provide a method for treating and / or preventing osteoporosis using teriparatide or a salt thereof, and an agent for treating and / or preventing osteoporosis containing teriparatide or a salt thereof as an active ingredient, which is excellent in safety and / or effectiveness.

[0053] Means for solving problems

[0054] One embodiment of the osteoporosis therapeutic and / or preventive agent and osteoporosis therapeutic and / or preventive method of the present invention 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.

[0055] These therapeutic and / or preventive agents for osteoporosis and therapeutic and / or preventive methods for osteoporosis show excellent safety and / or effectiveness.

[0056] That is, the present invention relates to the following inventions and the like.

[0057] [1] An agent for treating and / or preventing osteoporosis, comprising teriparatide or a salt thereof as an active ingredient, wherein 28.2 μg of teriparatide or a salt thereof is administered twice a week.

[0058] [2] The therapeutic and / or preventive agent for osteoporosis according to [1] above, wherein the interval between two administrations within a week (excluding the administration day) is 2 days and 3 days.

[0059] [3] An osteoporosis therapeutic and / or preventive agent as described in [1] above, wherein, when n is the number of weeks during which administration is performed twice a week and m is the number of weeks during which the interval between two administrations in one week is 2 days and 3 days (excluding the administration day), (m / n)×100(%) is 70% or more.

[0060] [4] The agent for treating and / or preventing osteoporosis according to any one of [1] to [3] above, wherein the agent is administered subcutaneously.

[0061] [5] The osteoporosis therapeutic and / or preventive agent according to any one of [1] to [4] above, wherein the agent is administered to a patient whose lumbar vertebrae bone density is less than 60% of the average value of young adults.

[0062] [6] The therapeutic and / or preventive agent for osteoporosis according to any one of [1] to [4] above, wherein the agent is administered to a patient who has previously had one vertebral fracture.

[0063] [7] The osteoporosis therapeutic and / or preventive agent according to any one of [1] to [4] above, wherein the agent is administered to a patient having a serum osteocalcin concentration of less than 15.2 (ng / mL).

[0064] [8] The therapeutic and / or preventive agent for osteoporosis according to any one of [1] to [4] above, wherein the agent is administered to a patient who is 80 years of age or older.

[0065] [9] The therapeutic and / or preventive agent for osteoporosis according to any one of [1] to [4] above, wherein the agent is administered to males.

[0066]

[10] The therapeutic and / or preventive agent for osteoporosis according to any one of [1] to [4] above, wherein the agent is administered to osteoporosis patients with a high risk of fracture.

[0067]

[11] The osteoporosis therapeutic and / or preventive agent according to any one of [1] to [4] above, wherein the agent is administered to osteoporosis patients who have all the risk factors for fractures, including advanced age, previous fractures, and low bone density.

[0068]

[12] The osteoporosis treatment and / or prevention agent according to any one of [1] to [4] above, wherein the agent is administered to an osteoporosis patient who satisfies the following conditions (1) to (3):

[0069] (1) Aged 65 or above;

[0070] (2) previous vertebral fractures of more than 1 but less than 5;

[0071] (3) Lumbar spine bone density is less than 80% of the average value of young adults.

[0072] Effects of the Invention

[0073] According to the present invention, there are provided a therapeutic and / or preventive agent for osteoporosis containing teriparatide or a salt thereof as an active ingredient and a therapeutic and / or preventive method for osteoporosis that are excellent in safety and / or efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] Figure 1 The figure shows an example of a dosing schedule when the osteoporosis therapeutic agent of the present invention is administered twice a week for 2 weeks with the dosing intervals being 1 day and 6 days (if the dosing day is not included, the dosing intervals are 0 and 5 days), 2 days and 5 days (if the dosing day is not included, the dosing intervals are 1 day and 4 days), or 3 days and 4 days (if the dosing day is not included, the dosing intervals are 2 days and 3 days).

[0075] Figure 2This is a diagram showing an example of a dosing schedule when the osteoporosis therapeutic agent of the present invention is administered twice a week for 2 weeks with dosing intervals of 3 and 4 days (2 and 3 days apart when dosing days are excluded).

[0076] Figure 3 FIG is a diagram schematically showing a treatment plan in an embodiment of the present invention. Figure 4 to Figure 28 These are graphs related to the test results of the examples. Details of each graph will be described below.

[0077] Figure 4 It is a graph showing the change in the average value (%) of the rate of change of lumbar vertebrae bone density (2nd to 4th lumbar vertebrae) after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks. The horizontal axis is the number of weeks of administration, and the vertical axis represents the average value (%) of the rate of change since the start. "BL" means baseline. "Final" refers to the "final time of treatment" which is used to represent the rate of change (%) of lumbar vertebrae bone density (2nd to 4th lumbar vertebrae) at the end of treatment for each patient, including the rate of change (%) of lumbar vertebrae bone density (2nd to 4th lumbar vertebrae) of patients who discontinued treatment midway through 48 weeks. The numerical values ​​shown in the 2 rows of the lower paragraph refer to the number of treated patients in each week. "**" means p<0.01.

[0078] Figure 5 This is a graph showing the change in the median value (%) of the serum CTX after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks. The horizontal axis is the number of weeks of administration, and the vertical axis represents the median value (%) of the change rate since the start. "BL" means baseline. The values ​​shown in the 2 rows of the lower section refer to the number of patients examined in each week.

[0079] Figure 6 This is a graph showing the change in the median value (%) of the serum NTX after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the median value (%) of the change rate since the start. "BL" means baseline. The values ​​shown in the two rows in the lower section refer to the number of patients examined in each week.

[0080] Figure 7 This is a graph showing the change in the median value (%) of the change rate of NTX in urine after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the median value (%) of the change rate since the start. "BL" means baseline. The values ​​shown in the two rows in the lower section refer to the number of patients examined in each week.

[0081] Figure 8It is a graph showing the change in the median value (%) of the rate of change of serum OC (osteocalcin) after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the median value (%) of the rate of change since the beginning. "BL" means baseline. The numerical values ​​shown in the 2 rows of the lower section refer to the number of patients examined in each week. "*" indicates Wilcoxon rank sum test p<0.05, and "**" indicates Wilcoxon rank sum test p<0.01.

[0082] Fig. 9 It is a graph showing the change of the median value (%) of the rate of change of serum P1NP after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks. The horizontal axis is the number of weeks of administration, and the vertical axis represents the median value (%) of the rate of change since the beginning. "BL" means baseline. The numerical values ​​shown in the 2 rows of the lower section refer to the number of patients examined in each week. "*" indicates Wilcoxon rank sum test p < 0.05, and "**" indicates Wilcoxon rank sum test p < 0.01.

[0083] Fig.10 This is a graph showing the change in the average value (%) of the lumbar vertebrae bone density (2nd to 4th lumbar vertebrae) after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks, classified according to the proportion of compliance with the administration interval being 70% or more and less than 70%. The horizontal axis is the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0084] Fig.11 This is a graph showing the change in the average value (%) of the lumbar vertebrae bone density (2nd to 4th lumbar vertebrae) after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks, classified according to the proportion of compliance with the administration interval being 75% or more and less than 75%. The horizontal axis is the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0085] Fig.12 This is a graph showing the change in the average value (%) of the lumbar vertebrae bone density (2nd to 4th lumbar vertebrae) after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks, classified according to the proportion of compliance with the administration interval being 80% or more and less than 80%. The horizontal axis is the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0086] Fig.13 This is a graph showing the change in the average value (%) of the lumbar vertebrae bone density (2nd to 4th lumbar vertebrae) after 48 weeks of administration of the osteoporosis therapeutic agent of the present invention to osteoporosis patients, classified according to the proportion of compliance with the administration interval being 85% or more and less than 85%. The horizontal axis is the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0087] Fig.14 This is a graph showing the change in the average value (%) of the lumbar vertebrae bone density (2nd to 4th lumbar vertebrae) after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks, classified according to the proportion of compliance with the administration interval being 90% or more and less than 90%. The horizontal axis is the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0088] Fig.15 This is a graph showing the change in the average value (%) of the femoral neck bone density after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks, classified according to the proportion of compliance with the administration interval of 70% or more and less than 70%. The horizontal axis is the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0089] Fig.16 This is a graph showing the change in the average value (%) of the femoral neck bone density after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks, classified according to the proportion of compliance with the administration interval of 75% or more and less than 75%. The horizontal axis is the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0090] Fig.17 This is a graph showing the change in the average value (%) of the femoral neck bone density after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks, classified according to the proportion of compliance with the administration interval being 80% or more and less than 80%. The horizontal axis is the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0091] Fig.18This is a graph showing the change in the average value (%) of the femoral neck bone density after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks, classified according to the proportion of compliance with the administration interval being 85% or more and less than 85%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0092] Fig.19 This is a graph showing the change in the average value (%) of the femoral neck bone density after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks, classified according to the proportion of compliance with the administration interval being 90% or more and less than 90%. The horizontal axis is the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0093] Fig. 20 This is a graph showing the change in the average value (%) of the whole bone density of the proximal part of the femur after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks, classified according to the proportion of compliance with the administration interval of 70% or more and less than 70%. The horizontal axis is the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0094] Fig.21 This is a graph showing the change in the average value (%) of the whole bone density of the proximal part of the femur after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks, classified according to the proportion of compliance with the administration interval of 75% or more and less than 75%. The horizontal axis is the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0095] Fig. 22 This is a graph showing the change in the average value (%) of the whole bone density of the proximal femur after the osteoporosis therapeutic agent of the present invention was administered to osteoporosis patients for 48 weeks, classified according to the proportion of compliance with the administration interval of 80% or more and less than 80%. The horizontal axis is the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0096] Fig.23This is a graph showing the change in the average value (%) of the whole bone density of the proximal part of the femur after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks, classified according to the proportion of compliance with the administration interval being 85% or more and less than 85%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0097] Fig.24 This is a graph showing the change in the average value (%) of the whole bone density of the proximal part of the femur after the osteoporosis therapeutic agent of the present invention is administered to osteoporosis patients for 48 weeks, classified according to the proportion of compliance with the administration interval of 90% or more and less than 90%. The horizontal axis is the number of weeks of administration, and the vertical axis represents the average value (%) of the change rate since the start. The values ​​shown in the two rows of the lower section refer to the number of patients analyzed in each week.

[0098] Fig.25 This is a graph showing the average value (%) of the change rate of lumbar vertebrae bone density (2nd to 4th lumbar vertebrae) observed 48 weeks after the start of administration, after osteoporosis patients who showed compliance results of more than each specific value (70%, 75%, 80%, 85%, 90%) were administered the osteoporosis therapeutic agent of the present invention.

[0099] Fig.26 This is a graph showing the fracture incidence rate (%) of clinical fractures after administration of the osteoporosis therapeutic agent of the present invention in osteoporosis patients showing compliance performance of more than each specific value (70%, 75%, 80%, 85%, 90%) for each compliance rate of 2-3 day dosing interval.

[0100] Fig. 27 This is a graph showing the median value (%) of the change rate of OC observed 4 weeks after the start of administration, after administration of the osteoporosis therapeutic agent of the present invention, etc., for osteoporosis patients who showed compliance results of each specific value (70%, 75%, 80%, 85%, 90%) or more for each 2-3 day dosing interval.

[0101] Fig.28 This is a graph showing the occurrence rate (%) of nausea (side effect) after administration of the osteoporosis therapeutic agent of the present invention in osteoporosis patients showing compliance performance of each specific value (70%, 75%, 80%, 85%, 90%) or more for each rate of compliance with the 2-3 day dosing interval.

[0102] Fig.29 It is the basic dosing regimen for the test drug group and the control drug group. DETAILED DESCRIPTION

[0103] The present invention will be described in detail below based on specific embodiments. However, the present invention is not limited to the following embodiments and can be implemented in any manner within the scope of the present invention.

[0104] (1) Teriparatide or its salt (hereinafter sometimes referred to as active ingredient):

[0105] In the present invention, human PTH (1-34) is a peptide represented by a partial amino acid sequence consisting of amino acid residues at positions 1 to 34 as viewed from the N-terminal side in the amino acid sequence of human PTH (1-84) which is human parathyroid hormone.

[0106] In the present invention, teriparatide refers to free human PTH (1-34). Teriparatide may be in the form of a salt.

[0107] In the present invention, as the salt of teriparatide, any salt formed from teriparatide and one or more volatile organic acids can be cited. As volatile organic acids, trifluoroacetic acid, formic acid, acetic acid, etc. can be exemplified. Regarding the ratio of the free teriparatide and the volatile organic acid when forming a salt, there is no particular limitation as long as the salt can be formed. Among them, acetic acid is preferred as the volatile organic acid. That is, as the salt of teriparatide in the present invention, teriparatide acetate can be preferably exemplified.

[0108] Teriparatide or a salt thereof can be produced by a method known per se (Patent Documents 1 to 3, etc.).

[0109] (2) Dosage:

[0110] The dosage of the active ingredient contained in the therapeutic and / or preventive agent for osteoporosis of the present invention and used in the therapeutic and / or preventive method for osteoporosis of the present invention per administration is not particularly limited, but the following numerical values ​​can be preferably exemplified.

[0111] That is, the dosage of the active ingredient per administration is more preferably 20 μg or more, 25 μg or more, 27 μg or more, or 28 μg or more. In addition, the dosage of the active ingredient contained in the osteoporosis treatment and / or prevention agent of the present invention per administration is preferably 40 μg or less, more preferably 35 μg or less or 30 μg or less.

[0112] The dosage of the active ingredient per administration is preferably 28.2 μg or 29.2 μg in terms of teriparatide. When the teriparatide used is acetate, the dosage after adding the amount of acetic acid can be exemplified. For example, when teriparatide pentaacetate is used, the dosage of the active ingredient per administration is preferably 30.3 μg or 31.3 μg in terms of teriparatide acetate. Therefore, in the present invention, the term "28.2 μg of teriparatide or its salt is administered per administration" means that the dosage of the salt of teriparatide per administration is 28.2 μg in terms of teriparatide, which is 30.3 μg in the case of teriparatide acetate.

[0113] (3) Dosing frequency-dosing interval:

[0114] The therapeutic and / or preventive agent for osteoporosis of the present invention and the therapeutic and / or preventive method for osteoporosis of the present invention are characterized in that the drug is administered twice a week.

[0115] When the osteoporosis therapeutic agent of the present invention is administered twice a week, the dosing interval within a week may be: 1) every 1 day and 6 days (if the dosing day is not included, it is every 0 and 5 days); 2) every 2 days and 5 days (if the dosing day is not included, it is every 1 day and 4 days); or 3) every 3 days and 4 days (if the dosing day is not included, it is every 2 days and 3 days) ( Figure 1 ).

[0116] The interval between administrations within a week is not particularly limited, but the most preferred intervals are 3 days and 4 days (2 days and 3 days if the administration day is not included).

[0117] If the dosage regimen lasts for 2 weeks from the first administration, the dosage interval within one week is specifically described as every 3 days and 4 days (if the dosage day is not included, it is every 2 days and 3 days), then the first dosage week (first week) can be administered twice a week by administering on the 4th or 5th day from the first administration date, and then the second week can be administered twice a week by administering on the 8th day, the 11th day, or the 12th day. Figure 2 ).

[0118] The time of administration is not particularly limited, and it can be daytime or nighttime. When the time of administration is daytime, the administration can be in the morning or in the afternoon. However, when other therapeutic drugs or basic drugs (Ca, vD agents, etc.) are used in combination, it is more preferred that the administration times do not overlap with each other.

[0119] When n is the number of weeks during which the osteoporosis therapeutic agent of the present invention is administered twice a week, and m is the number of weeks during which the interval between two administrations in a week is 3 days and 4 days (2 and 3 days when the administration day is not included), (m / n)×100(%) may be a certain value or more, and examples of the lower limit of the ratio include 50%, 60%, 70%, 75%, 80%, 85%, 90%, and 95%, and the lower limit of the ratio is preferably 80% or more, and more preferably 90% or more.

[0120] For example, when the osteoporosis therapeutic agent of the present invention is administered twice a week for 34 days, and the intervals between the two administrations in a week are 3 and 4 days (2 and 3 days when the administration day is not included) for 2 weeks, the above (m / n)×100 is calculated as 2÷(34÷7)×100, which is about 41.2(%).

[0121] (4) Administration route-administration site:

[0122] The administration route of the osteoporosis therapeutic and / or preventive agent and the osteoporosis therapeutic and / or preventive method of the present invention is not particularly limited, and the agent may be administered intravenously, subcutaneously, or intramuscularly. Among them, subcutaneous administration is preferably exemplified.

[0123] The administration site of the osteoporosis treatment and / or prevention agent of the present invention and the osteoporosis treatment method and / or prevention method of the present invention is also not particularly limited, and can be administered to the upper arm, thigh or abdomen, for example. However, in the second and subsequent administrations, it is preferred to administer at a site at least 3 cm away from the last administration site. In addition, before administration, the administration site and its surroundings are pinched by hand to bulge from the skin surface, thereby making administration easier.

[0124] (5) During medication:

[0125] The administration period of the osteoporosis therapeutic and / or preventive agent of the present invention and the osteoporosis therapeutic and / or preventive method of the present invention is not particularly limited and can be appropriately determined according to the prescription of the patient's attending physician or the like.

[0126] The lower limit of the administration period is not particularly limited, and as the administration period, for example, preferably 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 can be exemplified. The upper limit of the administration period is also not limited, and as the upper limit of the administration period, for example, within 5 years, within 4 years, within 3 years, or within 2 years can be appropriately cited.

[0127] (6) Disease-patient:

[0128] (6-1) Diseases:

[0129] One of the characteristics of the therapeutic and / or preventive agent for osteoporosis of the present invention and the therapeutic and / or preventive method for osteoporosis of the present invention is that the agent is administered for the purpose of treating and / or preventing osteoporosis.

[0130] Osteoporosis in the present invention refers to "a skeletal disease characterized by decreased bone strength and an increased risk of fracture" (Non-Patent Document 1; definition in the NIH Consensus Conference in 2000), and includes both primary osteoporosis and secondary osteoporosis.

[0131] As primary osteoporosis, catagen osteoporosis (postmenopausal osteoporosis and senile osteoporosis), idiopathic osteoporosis (osteoporosis after pregnancy, juvenile osteoporosis, etc.) can be exemplified. Secondary osteoporosis is osteoporosis caused by reasons such as specific diseases or medicaments, and as reasons, specific medicaments, rheumatoid arthritis, diabetes, hyperthyroidism, sexual dysfunction, disuse, nutrition, other congenital diseases, etc. can be cited. As specific medicaments, for example, steroids can be cited. The diagnostic criteria for primary osteoporosis are known (Non-patent literature 10).

[0132] As the osteoporosis of the present invention, osteoporosis with a high risk of fracture can be preferably mentioned. Osteoporosis with a high risk of fracture can be patients with risk factors such as low bone density, previous fractures, advanced age, and family history of femoral neck fracture (Non-Patent Document 9).

[0133] As described above, as a drug with the efficacy / effect of osteoporosis with a high risk of fracture, a preparation for daily administration and a preparation for once-weekly administration containing teriparatide or a salt thereof as an active ingredient have been developed, and they have been approved for sale and are actually used in clinical sites. In addition, the development of human anti-sclerostin antibodies has also been promoted as a therapeutic drug for osteoporosis with a high risk of fracture. Based on these circumstances, etc., those skilled in the art can easily and clearly identify osteoporosis with a high risk of fracture.

[0134] As a tool for evaluating the absolute risk of fracture for an individual, FRAX (registered trademark) of WHO (World Health Organization) is known, which can calculate the probability (%) of fracture occurrence for an individual in the next 10 years. In daily diagnosis and treatment, it can be used as a screening method to identify potential high-risk fracture patients among asymptomatic elderly people diagnosed by medical institutions.

[0135] (6-2) Patients:

[0136] The osteoporosis patient of the present invention may be an osteoporosis patient having at least one of the above-mentioned fracture risk factors. As such a patient, an osteoporosis patient having three fracture risk factors of advanced age, previous fracture, and low bone density can be preferably exemplified.

[0137] In addition, the osteoporosis patients of the present invention may also be osteoporosis patients whose at least one risk factor among the above-mentioned fracture risk factors meets specific conditions (for example: below a specific threshold, above a specific threshold, within a specific numerical range, presence or absence, etc.).

[0138] Among them, the osteoporosis patient of the present invention is preferably an osteoporosis patient with a high risk of fracture. As such an osteoporosis patient with a high risk of fracture, an osteoporosis patient satisfying the following three conditions can be preferably exemplified.

[0139] 1)Above 65 years old.

[0140] 2) The patient has had more than one previous fracture.

[0141] 3) Lumbar spine bone density is less than 80% of the Young Adult Mean (sometimes also called YAM).

[0142] Here, as the previous fracture, the previous vertebral fracture can be preferably cited, and as the number of previous fractures, it can be preferably more than 1 and less than 5. In addition, the previous vertebral fracture can also be a previous vertebral fracture with slight deformation (grade 1), moderate deformation (grade 2) or high deformation (grade 3) (Non-patent Document 9).

[0143] A specific example of level 1 is a mild fracture in which the vertebral height is reduced by 20-25%. A specific example of level 2 is a moderate fracture in which the vertebral height is reduced by 25-40%. A specific example of level 3 is a high fracture in which the vertebral height is reduced by more than 40%.

[0144] The osteoporosis patient of the present invention may be an osteoporosis patient who does not belong to the group of patients satisfying at least any one of the following six conditions.

[0145] 1) Patients considered to be at high risk of osteosarcoma.

[0146] 2) Patients with hypercalcemia.

[0147] 3) Patients with primary malignant bone tumors or metastatic bone tumors.

[0148] 4) Patients with metabolic bone diseases other than osteoporosis.

[0149] 5) Patients with a history of allergy to the active ingredient of the therapeutic and / or preventive agent for osteoporosis of the present invention or other teriparatide preparations.

[0150] 6) Pregnant women or women who may be pregnant.

[0151] Patients considered to have a high risk of developing osteosarcoma include, for example, patients with Paget's disease of bone, patients showing high alkaline phosphatase levels, children and young adults with unclosed epiphyses, and patients who have received radiation therapy that is believed to affect bones.

[0152] In addition, the osteoporosis patient of the present invention may be an osteoporosis patient who does not belong to the group of patients satisfying at least any one of the following five conditions.

[0153] 1) Patients with hypotension.

[0154] 2) Patients with renal impairment.

[0155] 3) Patients with severe heart disease.

[0156] 4) Patients with severe liver dysfunction.

[0157] 5) Patients with urethral stones and patients with a history of such diseases.

[0158] Alternatively, the osteoporosis patient of the present invention may be an osteoporosis patient with mild or moderate renal impairment. Normal renal function, impairment and the degree of impairment can be distinguished based on creatinine clearance. Specifically, a creatinine clearance of 80 mL / min or more can be judged as normal renal function, 50 mL / min or more and less than 80 mL / min can be judged as mild renal impairment, and 30 mL / min or more and less than 50 mL / min can be judged as moderate renal impairment. As a method for calculating creatinine clearance, for example, the Cockcroft-Gault formula (male: (140-age)×weight / (72×serum creatinine value), female: 0.85×(140-age)×weight / (72×serum creatinine value)) can be cited as an example.

[0159] In addition, the osteoporosis patient of the present invention may also be an osteoporosis patient in which at least any one of the following 18 factors possessed by the patient satisfies specific conditions (for example: below a specific threshold, above a specific threshold, in a specific numerical range, category, presence or absence, etc.).

[0160] 1) Gender.

[0161] 2) Age.

[0162] 3) Height.

[0163] 4) Weight.

[0164] 5)BMI.

[0165] 6) Number of years since menopause (limited to females and patients with amenorrhea).

[0166] 7) History of non-vertebral fracture injury after the age of 50 (limited to patients over 50 years old).

[0167] 8) History of non-vertebral fracture injury without obvious external force after the age of 50 (limited to patients over 50 years old).

[0168] 9) Past history of disease that may affect bone metabolism.

[0169] 10) Smoking.

[0170] 11) Alcohol intake.

[0171] 12) History of femur fracture in parents.

[0172] 13) Pro-therapeutic drugs for osteoporosis.

[0173] 14) 25-Hydroxyvitamin D.

[0174] 15) Number of previous vertebral fractures.

[0175] 16) Lumbar spine bone density (YAM conversion value) (%).

[0176] 17) Femoral neck bone density (YAM conversion value) (%).

[0177] 18) Whole-body bone density of the proximal femur (YAM conversion value) (%).

[0178] For example, the osteoporosis patients of the present invention can also be the following patients, etc.: male or female patients, patients aged 65 years or older and younger than 75 years, patients aged 75 years or older and younger than 80 years, patients aged 80 years or older, patients with lumbar vertebrae bone density (YAM conversion value) (%) less than 60%, 60% or more and less than 70%, or 70% or more and less than 80%, patients with zero previous vertebral fractures, patients with 1 previous vertebral fracture, patients with 2 to 3 previous vertebral fractures, patients with 4 to 5 previous vertebral fractures, patients with 6 or more previous vertebral fractures, etc.

[0179] The osteoporosis patient of the present invention may be an osteoporosis patient whose each item in at least any one of the following 26 clinical examination items satisfies specific conditions (eg, below a specific threshold, above a specific threshold, within a specific numerical range, etc.).

[0180] 1) Routine blood examination items (6 items in total) (red blood cell count, hemoglobin, hematocrit, white blood cell count, white blood cell classification, platelet count).

[0181] 2) Blood biochemistry examination 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).

[0182] 3) Urine examination items (6 items in total) (occult blood, protein, sugar, urobilinogen, bilirubin, pH).

[0183] Here, AST (GOT) refers to aspartate aminotransferase (Glutamic oxaloacetic transaminase), ALT (GPT) refers to alanine aminotransferase (Glutamic pyruvic transaminase), and CPK refers to creatine phosphokinase.

[0184] In addition, the osteoporosis patient of the present invention may also be an osteoporosis patient whose each item in at least any one of the vital signs (sitting systolic blood pressure, sitting diastolic blood pressure, pulse rate, etc.) satisfies specific conditions (for example: below a specific threshold, above a specific threshold, within a specific numerical range, etc.).

[0185] Alternatively, the osteoporosis patient of the present invention may be an osteoporosis patient who may produce anti-drug antibodies (e.g., antibodies against teriparatide or a salt thereof) or neutralizing antibodies (e.g., antibodies that may attenuate or eliminate the activity of teriparatide or a salt thereof) following administration of the therapeutic and / or preventive agent for osteoporosis of the present invention.

[0186] Furthermore, the osteoporosis patient of the present invention may be an osteoporosis patient in which at least any one of the following 12 markers satisfies specific conditions (eg, below a specific threshold, above a specific threshold, within a specific numerical range, etc.).

[0187] 1) Blood markers (osteocalcin, P1NP, NTX, CTX, calcium, inorganic phosphorus, albumin, 25-hydroxyvitamin D fraction).

[0188] 2) Urine markers (NTX, calcium, inorganic phosphorus, creatinine).

[0189] Here, P1NP refers to procollagen type I amino-terminal propeptide, NTX refers to crosslinked N-telopeptide of type I collagen, and CTX refers to type I collagen crosslinked C-telopeptide.

[0190] Examples of osteoporosis patients of the present invention include patients with a blood osteocalcin concentration of less than 15.2 (ng / mL), patients with a blood osteocalcin concentration of 15.2 (ng / mL) or more and less than 21.8 (ng / mL), and patients with a blood osteocalcin concentration of 21.8 (ng / mL) or more.

[0191] Alternatively, examples of osteoporosis patients of the present invention include patients whose blood osteocalcin concentration is less than 14.8 (ng / mL), patients whose blood osteocalcin concentration is 14.8 (ng / mL) or more and less than 21.9 (ng / mL), and patients whose blood osteocalcin concentration is 21.9 (ng / mL) or more.

[0192] In addition, osteoporosis patients of the present invention include, for example, 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.

[0193] Alternatively, osteoporosis patients of the present invention include, for example, 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.

[0194] The osteoporosis patient of the present invention may also be a patient with a history of treatment using a pro-therapeutic drug for osteoporosis. Pro-therapeutic drugs for osteoporosis include calcium agents, estrogen agents, SERMs (selective estrogen receptor modulators), active vitamin D3 agents, vitamin K2 agents, calcitonin agents, parathyroid hormone agents, bisphosphonates, and Denosumab.

[0195] Here, as SERM, raloxifene and bazedoxifene can be preferably exemplified, as active vitamin D3 agent, elcalciferol, alpha-calciferol and calcitriol can be preferably exemplified, as vitamin K2, tetraene menaquinone can be preferably exemplified. In addition, as bisphosphonate agent, etidronate, alendronate, risedronate, minodronate, ibandronate can be exemplified. As calcitonin agent, salmon calcitonin and elcatonin can be exemplified. As parathyroid hormone agent, daily administration preparation and weekly administration preparation with above-mentioned teriparatide or its salt as active ingredient can be enumerated.

[0196] In addition, the osteoporosis patient of the present invention may also be an osteoporosis patient suffering from other diseases, i.e., having complications. Other diseases include diabetes, hypertension, lipid abnormalities (hyperlipidemia, etc.), chronic kidney disease (CKD), rheumatoid arthritis, gout, hyperuricemia, dementia, cataract, presbycusis, urination disorder, cerebrovascular disease, ischemic heart disease, etc.

[0197] Alternatively, the osteoporosis patient of the present invention may be an osteoporosis patient in need of care.

[0198] (7) Use in combination:

[0199] The osteoporosis treatment and / or prevention agent of the present invention and the osteoporosis treatment and / or prevention method of the present invention can also be used in combination with other drugs. Other drugs can be administered together with the osteoporosis treatment and / or prevention agent of the present invention or sequentially (i.e., at separate times) in the same or different routes.

[0200] As other drugs, at least one of the above-mentioned pre-treatment drugs for osteoporosis can be cited. Alternatively, as other drugs, treatment and / or prevention drugs for the above-mentioned complications can also be cited. In addition, other drugs can also be basic drugs (Ca, vD agents, etc.).

[0201] As preferred basic drugs, vD3 (vitamin D3) agents, magnesium agents and calcium agents can be cited. They can be used in combination at will, or they can be made into a mixture. For example, a calcium agent mixed with vD3 and magnesium can be preferably exemplified as a basic drug. Such a mixture is preferably taken once a day after dinner, each time including vD3 400 IU, magnesium 30 mg and calcium 610 mg.

[0202] When the osteoporosis treatment and / or prevention agent of the present invention is provided as a test drug for clinical trials, the evaluation can also be implemented in a state where the subjects take the above-mentioned or corresponding basic drugs (non-patent document 15). It should be noted that the following ideas can also be considered: the reduction in fracture risk when vD and calcium are used in combination is unclear (non-patent document 25); when the basic drug is given to both the test drug group and the control drug group, the effect of the basic drug on the difference between the two groups related to effectiveness and safety is not substantially confirmed. Based on these situations, when the osteoporosis treatment and / or prevention agent of the present invention is used in the clinical field, vD and calcium agents do not necessarily have to be used.

[0203] (8) Preparation:

[0204] The therapeutic and / or preventive agent for osteoporosis of the present invention can take various preparation forms. Generally, from the perspective of stability, the preparation is preferably an injection containing pharmaceutically acceptable excipients and additives.

[0205] Excipients and additives are not particularly limited, and 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). The preparation may include a buffer, but may not include a buffer. The pH of the preparation may be appropriately adjusted, and may be, for example, 3.5 to 5.5.

[0206] The concentration of the active ingredient in the present preparation is not particularly limited, and may be, for example, 50 μg / mL or more, or 100 to 200 μg / mL.

[0207] When the present preparation is an injection, the present preparation can be produced by dissolving the active ingredient, excipients and additives in an appropriate solvent (sterile water, buffer solution, physiological saline, etc.), filtering and / or sterilizing using a filter, etc., and then filling and sealing in a cleaned and sterilized container.

[0208] Here, as the filling container, for example, an ampoule, a vial, a prefilled syringe, a bag, etc. can be exemplified. The material of the container is not particularly limited, and glass and plastic can be cited. From the aspects of strength, ease of handling, safety, etc., plastic can be preferably exemplified as the material of the container.

[0209] For example, it can be an automatic administration preparation in which a prefilled syringe with a needle prefilled with a drug solution is assembled into an automatic injector. The osteoporosis therapeutic agent of the present invention has sufficient safety and can therefore be made into a preparation for self-administration at home.

[0210] (9) Validity:

[0211] The main purpose of the therapeutic and / or preventive agent for osteoporosis of the present invention and the therapeutic and / or preventive method for osteoporosis of the present invention is to prevent or inhibit bone fractures.

[0212] (9-1) Prevention or inhibition of fractures:

[0213] The fractures of the present invention include any of disease fractures caused by osteoporosis, osteogenesis imperfecta, bone tumors, etc. and traumatic fractures caused by traffic accidents, collisions, etc. Preferably, fractures caused by osteoporosis are mentioned.

[0214] The fracture of the present invention includes any one of vertebral fracture and non-vertebral fracture. Non-vertebral fracture is not particularly limited, and for example, fractures of the proximal part of the femur, the distal end of the radius, the proximal part of the upper arm bone, the tibia, the pelvis, the ribs, etc. can be cited. As the fracture of the present invention, vertebral fracture (new vertebral fracture, aggravated vertebral fracture, etc.) can be preferably cited.

[0215] Usually, proximal femur fracture refers to hip fracture (hip fracture) of the elderly, which is understood as fracture different from fracture (fractures of the proximal part of the femur) of proximal femur (non-patent literature 9). As the fracture included in proximal femur fracture, for example, subchondral insufficiency fracture of the femoral head, femoral neck fracture, basal neck fracture, trochanteric fracture, subtrochanteric fracture (subtrochanteric fracture) (non-patent literature 9) can be enumerated.

[0216] It should be noted that, since the subchondral fracture of the femoral head is extremely rare and difficult to diagnose as a femoral neck fracture, it is also classified as either a femoral neck fracture or a femoral trochanteric fracture. Since the difference between a femoral trochanteric fracture and a subtrochanteric fracture is not obvious, a method for roughly dividing proximal femoral fractures into two categories, namely, a femoral neck fracture and a femoral trochanteric fracture, can also be used (Non-Patent Document 9). Since the proximal femoral part has the meaning of emphasizing its entirety, it is sometimes also referred to as the entire proximal femoral part.

[0217] Vertebral fracture is the most frequent osteoporotic fracture and is an important indicator for the diagnosis and treatment of osteoporosis. For the above reasons, its prevention or inhibition has a very high clinical significance (Non-patent Document 9). In addition, proximal femoral fracture is known to cause deterioration of life function and QOL and is also related to life prognosis (Non-patent Document 9), so it is sought to fully prevent and inhibit proximal femoral fracture.

[0218] Vertebral fractures can be determined as morphological fractures by the degree of vertebral deformation regardless of the presence or absence of clinical symptoms (Non-Patent Document 9). Morphological fractures can be classified into previous fractures and new fractures.

[0219] A new fracture can be determined as a new fracture by comparing X-ray images at two moments, and a previous fracture can be a fracture determined by the degree of deformation of the vertebral body at a certain moment before the start of treatment. Among new fractures, a fracture in which a vertebral body that was not deformed before the start of treatment but deformed after the start of treatment is regarded as a new vertebral fracture, and a fracture in which the degree of vertebral deformation is enhanced after the start of treatment can also be distinguished as a worsening fracture. In the present application specification, new vertebral fractures and worsening vertebral fractures are recorded by distinguishing them in this way.

[0220] The vertebral fractures of the present invention include any one of new vertebral fractures and aggravated vertebral fractures. For example, the degree of deformation can be classified based on the overall morphology of the vertebral body, usually set as level 0 (normal), level 1 (vertebral height is reduced by about 20-25% and vertebral area is reduced by 10-20%), level 2 (vertebral height is reduced by about 25-40% and vertebral area is reduced by 20-40%), and level 3 (vertebral height is reduced by about 40% or more and vertebral area is reduced by more than 40%). The distinction between new and aggravated can be implemented according to the level increase pattern based on the Genant's judgment criteria. Specifically, when a change from level 0 to level 1, 2 or 3 is confirmed, it is diagnosed as a new vertebral fracture; when a change from level 1 to level 2 or 3, or from level 2 to level 3 is confirmed, it can be regarded as an aggravated fracture.

[0221] Among the fractures of the present invention, the fractures 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 the present application specification, clinical non-vertebral fractures are referred to as non-vertebral fractures. Clinical symptoms such as acute pain in the waist and back can be confirmed by the subject's complaint.

[0222] The fracture evaluation method using X-ray images or MRI is known per se, and for example, there are known quantitative evaluation methods (QM method) and semi-quantitative evaluation methods (SQ method). The SQ method was proposed by Genant et al. in 1993 and has been used in many clinical trials in Japan and abroad to date. Since its evidence has also been established, it can be used more preferably (non-patent document 11). In addition, the method of Wu et al. and the method of Fukunaga et al. (non-patent documents 11 to 13) can also be used.

[0223] When testing a therapeutic and / or preventive agent for osteoporosis, it is preferred to evaluate its fracture inhibitory effect. When evaluating the fracture inhibitory effect of a test drug, the fracture incidence of a control drug obtained by providing a control drug confirmed to have fracture inhibitory properties based on past clinical data to the same test and implementing the same test is compared with the fracture incidence of the test drug; the untreated fracture incidence of subjects in the same test, which is inferred based on past clinical data, is compared with the fracture incidence of the test drug; by implementing the above operations, etc., the fracture inhibitory effect (fracture risk reduction, etc.) of the test drug in the same test can be evaluated without providing a placebo control drug in the same test.

[0224] (9-2) Increase in bone density:

[0225] Bone strength is formed by two factors, bone density and bone quality. Generally, "bone density" explains about 70% of bone strength, and the remaining 30% can be explained by "bone quality" (Non-Patent Document 9). It is known that daily-administration preparations and once-weekly-administration preparations containing teriparatide or a salt thereof as an active ingredient have not only a fracture-inhibiting effect but also a bone density-increasing effect (Non-Patent Documents 4, 5, 8, 9).

[0226] Here, bone density typically refers to the amount of bone minerals in the lumbar spine. The lumbar spine is rich in spongy bones with a fast bone metabolism conversion rate, so the sensitivity of detecting changes in bone density caused by drug treatment is also high. In addition, in cases where it is difficult to evaluate the amount of bone minerals in the lumbar spine, the bone minerals of the radius, the second metacarpal bone, the femoral neck, and the calcaneus can be used to represent the bone density. In addition, the average value of young adults refers to the average value of bone density of 20 to 44 years old.

[0227] Bone density can be measured by a known method such as dual-energy X-ray absorptiometry, optical density measurement, photon absorptiometry, quantitative CT, or quantitative ultrasonic method.

[0228] The bone density change rate can be calculated, for example, by the following formula.

[0229] Bone density change rate at a certain time a (%) = {(bone density at that time - bone density at the start of drug administration) / bone density at the start of drug administration} × 100

[0230] In addition, the degree of bone atrophy in the present invention refers to the degree of bone loss on X-rays. The degree of bone atrophy is classified into no bone atrophy, bone atrophy degree I, bone atrophy degree II, and bone atrophy degree III. The no bone atrophy in the bone atrophy degree refers to a normal state, specifically, a state in which the trabecular structure cannot be identified because the longitudinal and transverse trabeculae are dense. Bone atrophy degree I refers to a state in which the longitudinal trabeculae are obvious, typically referring to a state in which the longitudinal trabeculae appear thinner but are still densely arranged, and the vertebral endplates also become obvious. Bone atrophy degree II in the bone atrophy degree refers to the following state: the longitudinal trabeculae become rough, the longitudinal trabeculae appear thick, are roughly arranged, and the vertebral endplates also become faint. Bone atrophy degree III in the bone atrophy degree refers to the following state: the longitudinal trabeculae also become unclear, and the vertebral shadow as a whole shows a blurred feeling, and the difference with the intervertebral disc shadow is reduced. Bone atrophy can be determined, for example, by a lateral X-ray image of the lumbar spine.

[0231] (9-3) Changes in bone metabolism markers:

[0232] Changes in bone metabolism markers are associated with the prevention or suppression of fractures and an increase in bone density. Therefore, when evaluating osteoporosis therapeutic agents from the perspective of effectiveness, it is considered useful to measure the bone metabolism marker values ​​in biological samples (blood samples, urine samples, etc.) from subjects and confirm their changes (e.g., the difference between the value before administration and the value after administration, etc.) (Non-Patent Document 9).

[0233] In order to evaluate the effectiveness of the osteoporosis therapeutic and / or preventive agent of the present invention, changes in bone metabolism markers, increases in bone density or suppression of fractures can be observed. In the twice-weekly dosing method of the present invention in which the dosing interval within a week is every 2 days and 3 days (excluding the dosing day), it is preferred to evaluate the effectiveness by directly observing the increase in bone density or the suppression of fractures.

[0234] Bone metabolism markers can be roughly divided into bone formation markers and bone resorption markers. Bone formation markers are substances produced directly or indirectly by osteoblasts at various stages of osteoblast differentiation, and known ones include osteocalcin and P1NP. Bone resorption markers are substances related to osteoclast activation and bone resorption, and known ones include NTX and CTX.

[0235] In the past, regarding the daily osteoporosis treatment using teriparatide, the divergence between bone formation markers and bone resorption markers, which is particularly confirmed to increase rapidly from the start of administration, was called the "anabolic window", which is considered to be the mechanism of bone density increase from the early stage of administration (Non-patent Document 24). In the osteoporosis treatment and / or prevention agent of the present invention, the change of bone metabolism markers, such as the "anabolic window", particularly in the early stage of administration (e.g., within several months from the start of administration) can also be used as an indicator for treatment monitoring.

[0236] However, in the twice-weekly dosing method of the present invention, in which the dosing interval within a week is 2 days and 3 days (excluding the dosing day), the correlation between bone metabolism markers and effectiveness can be clearly distinguished from the previous teriparatide treatment method. Therefore, in the same dosing method, when evaluating effectiveness, it is more preferable to directly observe the increase in bone density or the inhibition of fracture rather than the change in bone metabolism markers.

[0237] Furthermore, according to a study on ovariectomized rats (Non-Patent Documents 14 and 15), which is a common osteoporosis model, it has been reported that when the frequency of teriparatide administration is high, the voids in the cortical bone increase in accordance with the dosage (Non-Patent Document 14).

[0238] In addition, there are reports that teriparatide can be used as a therapeutic drug for osteoporosis with a high risk of fracture, and in patients who are the subjects, the voids in the cortical bones increase due to advanced age or condition; it is reported that in order to maximize the therapeutic effect of teriparatide, a treatment strategy that takes into account the patient's condition and the characteristics of the pharmacological action of teriparatide is necessary; etc. (Non-Patent Document 14).

[0239] Therefore, in the treatment or prevention of the present invention, the following method is preferred: the bone formation markers associated with bone density increase or fracture inhibition rate are increased, and the blood concentration or urine concentration of the bone resorption markers closely related to the cavitation and porosity of cortical bone is reduced or increased over time. As bone resorption markers closely related to the cavitation and porosity of cortical bone, NTX and CTX can be exemplified. In addition, as such a method of the present invention, it can be a method of appropriately vacating the interval between administration and administration to the extent that bone resorption is not continuously hyperactive during repeated administration, more specifically, for example, the treatment or prevention of 28.2 μg of the dosage can be exemplified, wherein the twice-weekly administration method of the present invention (wherein, 1 dosage is 28.2 μg of the dosage converted to teriparatide) and the administration interval within a week is 2 days and 3 days (excluding the administration day) of the administration method.

[0240] (10) Safety:

[0241] (10-1) Adverse events and side effects:

[0242] All undesirable or unexpected diseases and symptoms of the diseases occurring in a patient to whom a drug is administered can be referred to as adverse events (AEs).

[0243] Among adverse events, those in which the causal relationship with the drug cannot be denied can be referred to as side effects. Here, the causal relationship cannot be denied includes not only the reasonable possibility of confirming the causal relationship, but also the reasonable possibility that the causal relationship cannot be evaluated.

[0244] Adverse events can be roughly divided into serious adverse events and non-serious adverse events. The following six types of adverse events can be regarded as serious adverse events, and situations other than serious adverse events can be regarded as non-serious adverse events.

[0245] 1) Fatal (death).

[0246] 2) Life-threatening (risk of death).

[0247] 3) Hospitalization or prolonged hospitalization is required for treatment (hospitalization or extension of hospitalization).

[0248] 4) Suffering from persistent or marked impairment / dysfunction (disorder).

[0249] 5) Cause congenital anomalies (congenital anomalies).

[0250] 6) Other medically significant conditions (risk of disorder, serious conditions based on 1) to 4) above).

[0251] In addition, adverse events can be roughly divided according to their degree in addition to severity and causality. For example, the following three degrees can be considered.

[0252] 1) Mild: temporary and easily tolerated.

[0253] 2) Moderate: The degree that causes failure in routine activities.

[0254] 3) Height: The degree to which one is unable to carry out normal activities.

[0255] Alternatively, from the perspective of changes over time, the transition period of an adverse event can be further classified into, for example, recovered / resolved, recovering / resolving, not recovered / notresolved, recovered / resolved with sequelae, death, and unknown.

[0256] There is no particular limitation on the method for comparing a certain drug with other drugs based on safety. For example, the comparison can be made based on the frequency, severity, causal relationship, conversion period and / or degree of a certain adverse event. Alternatively, the two preparations can be compared based on the interruption of administration due to the adverse event as a whole or a part thereof or the side effect as a whole or a part thereof.

[0257] Adverse events may include abnormalities in clinical test values ​​and vital signs.

[0258] Adverse events are not particularly limited, and can be classified according to system organ classes (SOC). The system organ classes of adverse events can be exemplified as follows.

[0259] 1)Infections and infestations

[0260] 2) Gastrointestinal disorders

[0261] 3) Musculoskeletal and connective tissue disorders

[0262] 4) Injury, poisioning and procedural complications

[0263] 5) General disorders and administration site conditions

[0264] 6) Skin and subcutaneous tissue disorders

[0265] 7) Nervous system disorders

[0266] 8) Respiratory, thoracic and mediastinal disorders

[0267] 9) Eye disorders

[0268] 10) Metabolism and nutrition disorders

[0269] 11) Investigations (clinical examinations)

[0270] 12) Neoplasms benign, malignant and unspecified (inclcysts and polyps)

[0271] 13) Ear and labyrinth disorders

[0272] 14) Cardiac disorders

[0273] 15) Vascular disorders

[0274] As adverse events classified as "infectious diseases and parasitic diseases", pharyngitis and influenza can be exemplified. As adverse events classified as "nervous system disorders", headaches and floating vertigo can be exemplified. As adverse events classified as "respiratory, thoracic and mediastinal disorders", inflammation of the upper respiratory tract can be exemplified. As adverse events classified as "gastrointestinal disorders", nausea, vomiting, and constipation can be exemplified. As adverse events classified as "skin and subcutaneous tissue disorders", eczema can be exemplified. As adverse events classified as "musculoskeletal and connective tissue disorders", osteoarthritis can be exemplified. As adverse events classified as "general / systemic disorders and symptoms at the administration site", fatigue, bleeding at the injection site, and fever can be exemplified. As adverse events classified as "disorders, poisoning, and surgical complications", contusions can be exemplified.

[0275] As described above, it has been reported that nausea, vomiting, headache, etc. are often observed by administering teriparatide acetate (Non-Patent Document 9). It has also been reported that in a clinical trial using a preparation for daily administration containing teriparatide or a salt thereof as an active ingredient, dizziness was significantly higher than in the placebo group (Non-Patent Document 9), and it is also known that in preparations for daily administration containing teriparatide or a salt thereof as an active ingredient and preparations for once-weekly administration, shock, loss of consciousness accompanied by a temporary rapid drop in blood pressure, etc. may occur from immediately after administration to several hours later (Non-Patent Documents 4, 8).

[0276] Therefore, in the treatment or prevention of the present invention, it is preferred to suppress the frequency, severity and / or degree of at least one of the adverse events or side effects such as nausea, vomiting, headache, (floating) dizziness, shock, hypotension, and loss of consciousness as much as possible.

[0277] (10-2) Treatment duration:

[0278] As described above, regarding the medication status in the drug treatment of osteoporosis, it has been reported that 52.1% of patients have lost their bone within 5 years after the start of treatment. In addition, the reduction in fracture suppression due to insufficient compliance with medication, the increased need to use rehabilitation facilities, and the stagnation of medical cost reduction are also considered problems (Non-patent Document 9). As factors related to poor compliance with medication, the presence of pain, side effects, medication for gastrointestinal disorders, etc. can be exemplified (Non-patent Document 9). Moreover, on the other hand, regarding preparations with teriparatide or its salt as an active ingredient, a low treatment continuation rate has also been pointed out, and it is reported that the treatment continuation rate for 12 months is 34.9% (Non-patent Document 22).

[0279] Therefore, it is believed that providing a medical treatment using teriparatide or a salt thereof and exhibiting a higher treatment duration rate can not only improve the lives of individual patients, but also have high significance in public areas such as social welfare and medical economy.

[0280] As described above, in the treatment or prevention of the present invention, an aspect showing a high treatment sustainability rate is preferred.

[0281] [Example]

[0282] The present invention will be described in more detail below with reference to the following examples, but the present invention is not limited to the following examples and can be implemented in any manner without departing from the gist of the present invention.

[0283] (Example 1)

[0284] 1. Test method:

[0285] The subjects were randomly assigned to either the test drug group or the control drug group. Figure 3 As shown, each subject in the test drug group was administered with the test drug and the control drug placebo, and each subject in the control drug group was administered with the control drug and the test drug placebo. During the administration, subcutaneous administration was performed using a double-blind method for 48 weeks. In addition, the subjects in either group took 2 tablets of the standard combination drug once a day after dinner.

[0286] If each subject has used osteoporosis treatment drugs within 8 weeks before obtaining clinical trial consent, a washout will be implemented. During the washout, the day after the last dose / injection day of the previous treatment drug for osteoporosis treatment is used as the first day of the washout, and the start date of the clinical trial drug is 8 weeks (56 days) after the washout. However, in principle, the period from obtaining consent to the start of treatment with the clinical trial drug should not exceed 12 weeks (84 days).

[0287] If the responsible clinical trial doctor or clinical trial duty doctor determines that the subject meets the prescribed criteria after the start of treatment with the clinical trial drug, the clinical trial of the subject shall be terminated. The prescribed criteria are adverse events, lack of effect, inability to follow up, judgment of the responsible clinical trial doctor or clinical trial duty doctor, serious deviation from the clinical trial implementation plan, poor compliance with the administration of the clinical trial drug, complaint from the subject, or judgment of the client.

[0288] 1.1. Drugs to be tested:

[0289] The test drug is an automatic injector preparation containing 0.2 g of drug solution in one vial, and is a preparation that administers 28.2 μg of teriparatide (30.3 μg of teriparatide acetate) when the total amount of one vial is administered. The drug solution is pre-filled in a pre-filled syringe with a needle assembled in an automatic injector, which is a device used for subcutaneous injection of drug solution into the human body.

[0290] 1.2. Test drug placebo:

[0291] The test drug placebo is an automatic injector preparation that is indistinguishable from the test drug in appearance and does not substantially contain teriparatide.

[0292] 1.3. Comparator drug:

[0293] The control drug was a vial preparation, which was a freeze-dried injection preparation containing 63.3 μg of teriparatide (67.9 μg of teriparatide acetate) in one vial. It should be noted that when the drug solution obtained by adding 1 mL of Japanese Pharmacopoeia physiological saline solution and dissolving was administered using a syringe, the control drug was a preparation in which 56.5 μg of teriparatide was administered.

[0294] 1.4. Control drug placebo:

[0295] The control drug placebo is a freeze-dried injection preparation that is indistinguishable from the control drug in appearance and does not substantially contain teriparatide.

[0296] 1.5. Standard combined medication:

[0297] The standard combination medicine is a calcium preparation mixed with vitamin D3 and magnesium (New Calcichew (registered trademark) D3; sold by Nitto Chemical Industries, Ltd.; sold by Takeda Chemical Industries, Ltd.). Two tablets of the standard combination medicine contain 1525 mg of precipitated calcium carbonate (610 mg in terms of calcium), 118.4 mg of magnesium carbonate (30 mg in terms of magnesium), 400 IU of cholecalciferol (vitamin D3), and various additives.

[0298] 1.6. Frequency: 2 times a week:

[0299] The dosing interval at a frequency of twice a week is in principle 3 to 4 days apart (2 days apart, 3 days apart). The dosing interval (3 to 4 days apart) in principle here means that the dosing day of any one of the two consecutive dosings is taken as the first day, and another dosing is performed on the 4th or 5th day. For example, in the case of dosing on Monday of a certain week, as shown below, the next dosing day is in principle Thursday or Friday.

[0300] (An example of the principle dosing interval)

[0301] Dose on Monday Day 1

[0302] Tuesday Day 2

[0303] Wednesday Day 3

[0304] Administer on Thursday, Day 4 or Friday, Day 5

[0305] 1.7. Subjects:

[0306] The subjects were osteoporosis patients who had all three risk factors for fracture: "advanced age", "previous fractures", and "low bone density". More specifically, the subjects were primary osteoporosis patients who met all of the following conditions (1) to (6) (met the selection criteria) and did not meet any of the following conditions (7) to (25) (met the exclusion criteria). Since the subjects were osteoporosis patients who had all three risk factors for fracture: "advanced age", "previous fractures", and "low bone density" (met the following conditions (2) to (4)), they were osteoporosis patients with a high risk of fracture.

[0307] [1] Selection criteria:

[0308] (1) Patients diagnosed with primary osteoporosis based on the Diagnostic Criteria for Primary Osteoporosis (revised in 2012).

[0309] (2) Men and women who are 65 years of age or older at the time of consent.

[0310] (3) Patients with a history of 1 to 5 fractures in the Th4 to L4 (4th thoracic vertebra to 4th lumbar vertebra) of the vertebrae.

[0311] (4) Patients whose lumbar spine (L2-L4) bone density at the time of preliminary registration is less than 80% of the average value of young adults.

[0312] (5) External patients who can walk independently.

[0313] (6) Patients who have mastered the self-injection technique before the first administration of the test drug, etc. and are judged by the clinical trial responsible physician or clinical trial responsible physician to be able to manage and administer the test drug, etc.

[0314] [2]Excluded criteria:

[0315] (7) Patients diagnosed with secondary osteoporosis.

[0316] (8) Patients with diseases other than osteoporosis that cause bone loss.

[0317] (9) Patients with the following observations that are considered to affect the evaluation of lumbar spine bone density during X-ray observation.

[0318] Obvious vertebral fracture was confirmed in any of the lumbar vertebrae L2 to L4.

[0319] Significant bone sclerosis was observed in any of the lumbar vertebrae L2 to L4.

[0320] · Obvious lateral curvature, forward curvature, and backward curvature were confirmed.

[0321] Obvious deforming spondylosis changes were confirmed.

[0322] ・The inclusion of other foreign matter was judged as inappropriate by the bone evaluation committee.

[0323] It should be noted that the "bone evaluation committee" is a member of the "bone evaluation committee" set up to evaluate the bone mass and fracture of all patients equally. Each evaluation committee member is an expert in image diagnosis of osteoporosis.

[0324] (10) Patients who underwent vertebral surgery.

[0325] (11) Patients complaining of acute pain suspected of vertebral fracture {patients who have experienced acute low back pain or have experienced worsening pain since 12 weeks (84 days) before consent was obtained until the start of treatment and who have required additional treatment with sedatives and anti-inflammatory analgesics}.

[0326] (12) Patients for whom the reliability of the interview was judged to be low (at least excluding patients with dementia).

[0327] (13) Patients with severe renal disease, liver disease or heart disease (wherein, "severe renal disease" here means a serum creatinine value of 2 mg / dL or more in the test prescribed before preliminary registration, "severe liver disease" means an AST (GOT) or ALT (GPT) value of 2.5 times or more of the upper limit of the reference value or 100 IU / L or more in the test prescribed before preliminary registration, and "severe heart disease" means a judgment made with reference to Level 2 shown in the "Criteria for Classification of Severity of Side Effects of Pharmaceuticals (Pharmaceutical Safety Release No. 80, June 29, 1992)").

[0328] (14) Patients with a constitution that is prone to allergic symptoms such as bronchial asthma, rash (erythema, exanthema, etc.)

[0329] (15) Patients whose serum calcium level is 11.0 mg / dL or higher in the examination prescribed before preliminary registration.

[0330] (16) Patients whose alkaline phosphatase value in the examination prescribed before preliminary registration is more than twice the upper limit of the reference value.

[0331] (17) Patients with Paget’s disease of bone.

[0332] (18) Patients with primary malignant bone tumors or metastatic bone tumors, or with a history of such tumors.

[0333] (19) Patients with concurrent malignant bone tumors or a history of such tumors within the past 5 years.

[0334] (20) Patients who have received radiation therapy in the past that is believed to have an effect on bones.

[0335] (21) Patients who have received teriparatide preparations or anti-RANKL antibody preparations in the past.

[0336] (22) Patients who have received bisphosphonate preparations within 52 weeks (364 days) before obtaining consent (wherein, for drugs with a set interval period according to the drug's dosage, the number of days is the sum of that period and 52 weeks (364 days) before obtaining consent).

[0337] (23) Patients who have been administered other clinical trial drugs within 26 weeks (182 days) before obtaining consent.

[0338] (24) Patients who have received the following osteoporosis therapeutic drugs (A) to (G) on the day of obtaining consent (however, if they are able to take a washout (i.e., a break from the previous therapeutic drug, etc.) for 8 weeks (56 days) or more before starting treatment, they may be selected as subjects).

[0339] (A) Calcitonin preparations.

[0340] (B) Active vitamin D3 preparation.

[0341] (C) Vitamin K preparations.

[0342] (D) Ipriflavone preparations.

[0343] (E) Estrogen preparations.

[0344] (F) SERM preparations.

[0345] (G) Anabolic androgenic steroid preparations.

[0346] (25) Other patients who are judged as unsuitable by the clinical trial responsible physician or clinical trial responsibilities physician during the implementation of this clinical trial.

[0347] 1.8. Administration of drug to the test drug group and control drug group:

[0348] The subjects were randomly assigned to either the test drug group or the control drug group. Figure 3 As shown, each subject in the test drug group was administered with the test drug and the control drug placebo, and each subject in the control drug group was administered with the control drug and the test drug placebo. During the administration, subcutaneous administration was performed using a double-blind method for 48 weeks. In addition, the subjects in either group took 2 tablets of the standard combination drug once a day after dinner.

[0349] Each patient assigned to the test drug group received a subcutaneous injection of the test drug twice a week (self-injection into any part of the upper arm, thigh, or abdomen). The dosing interval is generally 3 to 4 days (2 days in between, 3 days in between). Furthermore, one vial of the control drug placebo was dissolved in 1 mL of Japanese Pharmacopoeia physiological saline solution when used, and the resulting solution was subcutaneously injected into the patient once a week (injection at the hospital).

[0350] Each patient assigned to the control drug group received a subcutaneous injection of a placebo twice a week (self-injection into any part of the upper arm, thigh, or abdomen). Furthermore, one vial of the control drug was dissolved in 1 mL of Japanese Pharmacopoeia physiological saline solution when used, and the resulting solution was subcutaneously injected into the patient once a week (injection at the hospital).

[0351] The main evaluation item for the effectiveness of the test is the change rate of lumbar spine bone density (2nd to 4th lumbar vertebrae).

[0352] Secondary evaluation items of the effectiveness of the trial are the change rate of femoral bone mineral density, the change rate of lumbar spine bone mineral density (1st to 4th lumbar vertebrae), the incidence of new vertebral fractures, the incidence of aggravated vertebral fractures, the incidence of (new and aggravated) vertebral fractures, the incidence of clinical fractures (clinical vertebral fractures, non-vertebral fractures), the incidence of fragility clinical fractures, the incidence of fragility non-vertebral fractures and bone metabolism markers.

[0353] The safety evaluation items of the trial were adverse events, vital signs, clinical examinations and immunogenicity.

[0354] 1.9. Determination of bone density change rate:

[0355] The measurement methods of the bone density change rates of lumbar vertebrae bone density and femur bone density are shown in the following Table 1-1.

[0356] [Table 1-1]

[0357] Table 1-1

[0358]

[0359] 1.10. Evaluation of vertebral fractures:

[0360] The evaluation method for vertebral fracture is shown in Table 1-2 below.

[0361] [Table 1-2]

[0362] Table 1-2

[0363]

[0364] 1.11. Evaluation of clinical fractures (clinical vertebral fractures and non-vertebral fractures):

[0365] A clinical fracture is defined as a case where the subject complains (clinical symptoms) from the start of treatment to 48 weeks later (at the time of discontinuation) and the clinical trial responsible physician or clinical trial responsible physician confirms a fracture through X-rays or MRI, etc. In particular, when the subject complains of acute pain in the lower back, X-rays are taken to confirm the presence of a fracture.

[0366] The evaluation contents included the date of fracture occurrence (the number of days on which the subject developed the clinical symptoms), the site of fracture (vertebral body, proximal part of femur, radius, upper arm bone, others), the presence or absence of large external force, the basis for judging the fracture (X-ray / MRI, information from other departments / other hospitals, others), and the date of X-ray / MRI imaging.

[0367] 1.12. Examination of bone metabolism markers:

[0368] The examination method of bone metabolism markers is shown in Tables 1-3 below.

[0369] [Table 1-3]

[0370] Table 1-3

[0371]

[0372] 1.13. Investigation of adverse events:

[0373] The responsible physician or clinical trial physician shall investigate adverse events based on spontaneous reports from subjects, medical interviews, and various tests from the date of obtaining consent from each subject to one week after the final date of administration.

[0374] The survey items include the name of the adverse event, the date of occurrence, the administration of the clinical trial drug, the date of disappearance, the conversion period, the severity classification, the reason for severity, the degree, the causal relationship with the clinical trial drug and the standard concomitant medication, the injection site in case of an adverse event, and whether the clinical trial was terminated.

[0375] 1.14. Determination of vital signs:

[0376] The method for measuring vital signs is shown in Tables 1-4 below.

[0377] [Table 1-4]

[0378] Table 1-4

[0379]

[0380] 1.15. Clinical examination:

[0381] The methods of clinical examination are shown in Tables 1-5 below.

[0382] [Table 1-5]

[0383] Table 1-5

[0384]

[0385] 1.16. Evaluation of immunogenicity:

[0386] The responsible clinical trial physician or clinical trial physician shall collect and store the test sample (blood) before the administration of the clinical trial drug on each test day. After the test sample is recovered, the anti-drug antibody against the clinical trial drug is measured. Only the specimens that are positive for anti-drug antibodies are measured for neutralizing antibodies.

[0387] 2. Test results:

[0388] 2.1. Target of effectiveness analysis:

[0389] There were 859 subjects who showed consent for treatment, of which 553 were registered for the clinical trial and received treatment, 76 discontinued treatment, and 477 completed treatment. The background (summary) of 551 of the 553 subjects who received treatment and were analyzed for effectiveness is shown in the following Table 2-1. Table 2-1 shows that there was no significant difference in background between the test drug group and the control drug group, and the risk of fracture was roughly the same.

[0390] [Table 2-1]

[0391] Table 2-1: Background of the subjects of effectiveness analysis (summary)

[0392]

[0393] 2.2. Average number of dosings and average dosing duration:

[0394] The average number of dosing and the average dosing period for the 553 subjects who received treatment are shown in the following Tables 2-2 and 2-3. It should be noted that regarding the average number of dosing, the subjects who were administered with the test drug as the actual drug (MN-10-T AI) were given a placebo of the control drug (MN-10-T placebo), and the subjects who were administered with the control drug as the actual drug (MN-10-T) were given a placebo of the test drug (MN-10-T AI placebo) ( Fig.29 ), so the average number of administrations of the four preparations, the actual drug of the test drug, the placebo of the control drug, the placebo of the test drug, and the actual drug of the control drug, was calculated.

[0395] [Table 2-2]

[0396] Table 2-2: Average number of medications (times)

[0397]

[0398] [Table 2-3]

[0399] Table 2-3: Average medication duration (weeks)

[0400] Average duration of medication Tested drug group 43.9 Control group 42.8

[0401] It can be considered that there is no significant difference in the average number of dosing times when comparing the actual drug of the test drug group with the test drug placebo of the control drug group, and when comparing the control drug placebo of the test drug group with the actual drug of the control drug group.

[0402] The average duration of administration was considered to be no different between the test drug group and the control drug group. It should be noted that the reason why it did not reach 48 weeks was that it included cases of discontinuation during the course of the treatment.

[0403] 2.3. Time-dependent changes in the average bone density of the lumbar spine, femoral neck, and proximal femoral region Transition:

[0404] The time transition of the average value of the bone density change rate of the lumbar spine (2nd to 4th lumbar vertebrae), lumbar spine (1st to 4th lumbar vertebrae), femoral neck and femoral proximal part of the whole in the effectiveness analysis subjects is shown in the following Tables 2-4 to 2-7. The numerical values ​​in the table represent the average value (%) of the change rate from the start.

[0405] In addition, the time transition of the average value of the bone density change rate of the lumbar vertebrae (the second to fourth lumbar vertebrae) among the analysis subjects of effectiveness is shown in Figure 4 .

[0406] [Table 2-4]

[0407] Table 2-4: Time transition of the average value (%) of the change rate of lumbar vertebrae bone density (2nd to 4th lumbar vertebrae)

[0408] 24 weeks later 48 Weeks Later final Tested drug group 5.0** 7.5** 7.3** Control group 3.8 6.0 5.9

[0409] **: p<0.01 (statistical analysis results based on t-Student test)

[0410] [Table 2-5]

[0411] Table 2-5: Time transition of the average value (%) of the change rate of lumbar vertebrae bone density (1st to 4th lumbar vertebrae)

[0412] 24 weeks later 48 Weeks Later final Tested drug group 4.8** 7.2** 7.1** Control group 3.5 5.5 5.4

[0413] **: p<0.01

[0414] [Table 2-6]

[0415] Table 2-6: Time course of the average value (%) of the change rate of femoral neck bone density

[0416] 24 weeks later 48 Weeks Later final Tested drug group 1.6 2.1 2.0 Control group 1.0 1.4 1.4

[0417] [Table 2-7]

[0418] Table 2-7: Time course of the average value (%) of the change rate of the whole bone density in the proximal part of the femur

[0419] 24 weeks later 48 Weeks Later final Tested drug group 1.3 1.8 1.8 Control group 1.0 1.3 1.3

[0420] Compared with the control drug, the test drug showed a higher rate of increase in lumbar spine bone density, femoral neck bone density, and total femoral proximal bone density. In particular, lumbar spine bone density increased significantly.

[0421] When comparing the treatment based on the test drug with the treatment based on the control drug, it is believed that the dosage of teriparatide per week is substantially the same. On the other hand, it has been reported that bone density and bone strength increase in accordance with the dosage of teriparatide per week (Non-patent Document 14). Therefore, it can be considered that the result that the treatment based on the test drug is considered to be more significant than the treatment based on the control drug can be clearly distinguished from the previous medical technology.

[0422] The subjects of effectiveness analysis were divided into subgroups based on the initial lumbar spine (2nd to 4th lumbar vertebrae) bone density or the number of previous vertebral fractures as indicators, and the results of the analysis of the average value of the lumbar spine (2nd to 4th lumbar vertebrae) bone density change rate at the final time are shown in the following Tables 2-8 and 2-9. The values ​​in the table represent the average value of the change rate from the initial time (%).

[0423] [Table 2-8]

[0424] Table 2-8: Average change rate of bone density of lumbar vertebrae (2nd to 4th lumbar vertebrae) at the final stage, classified by the bone density of lumbar vertebrae (2nd to 4th lumbar vertebrae) at the initial stage

[0425]

[0426] [Table 2-9]

[0427] Table 2-9: Average change rate of bone density at the final stage of lumbar spine (2nd to 4th lumbar vertebrae) classified by the number of previous vertebral fractures

[0428]

[0429] It has been reported that a 1 SD decrease in lumbar spine bone density increases the risk of vertebral fracture by 2.3 times (Non-Patent Document 9).

[0430] The increase in lumbar bone density caused by medication was analyzed using the initial lumbar bone density and the number of previous vertebral fractures as indicators. The results showed that as the initial lumbar bone density decreased, the increase in lumbar bone density caused by medication tended to increase; conversely, when the number of previous vertebral fractures increased, the increase in lumbar bone density caused by medication tended to decrease.

[0431] The subjects of effectiveness analysis were divided into subgroups based on the serum osteocalcin value at the start as an indicator, and the time transition of the average value of the bone density change rate of the lumbar spine (2nd to 4th lumbar vertebrae) and the femoral neck was analyzed and the results are shown in the following Tables 2-10 and 2-11. The values ​​in the table represent the average value of the change rate from the start (%).

[0432] [Table 2-10]

[0433] Table 2-10: Time transition of the average value (%) of the change rate of lumbar vertebrae bone density (2nd to 4th lumbar vertebrae)

[0434]

[0435] [Table 2-11]

[0436] Table 2-11: Time course of the average change rate of femoral neck bone density (%)

[0437]

[0438] The subjects of effectiveness analysis were divided into subgroups based on the initial blood P1NP value as an indicator, and the time course of the average value of the bone density change rate of the lumbar spine (2nd to 4th lumbar vertebrae) and the femoral neck was analyzed and the results are shown in the following Tables 2-12 and 2-13. The values ​​in the table represent the average value (%) of the change rate from the initial time.

[0439] [Table 2-12]

[0440] Table 2-12: Time transition of the average value (%) of the change rate of lumbar vertebrae bone density (2nd to 4th lumbar vertebrae)

[0441]

[0442] [Table 2-13]

[0443] Table 2-13: Time course of the average change rate of femoral neck bone density (%)

[0444]

[0445] 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 OC or P1NP concentration at the beginning (test drug group) by the average value of the bone density change rate at the end of the subgroup with the lowest OC or P1NP concentration at the beginning (control drug group) was calculated, and the results are shown in the following Table 2-14.

[0446] [Table 2-14]

[0447] Table 2-14:

[0448]

[0449] From the viewpoint of the effect of increasing the bone density of the femoral neck in patients with relatively low blood OC concentrations (eg, less than 15.2 (ng / mL)), treatment with the test drug is considered to be particularly excellent.

[0450] 2.4. Incidence of vertebral fractures:

[0451] The temporal changes of the incidence rates of new vertebral fractures and aggravated vertebral fractures based on the Kaplan-Meier method among the analysis subjects of effectiveness are shown in the following Tables 2-15 and 2-16.

[0452] [Table 2-15]

[0453] Table 2-15: Changes in the incidence of new vertebral fractures over time

[0454]

[0455] [Table 2-16]

[0456] Table 2-16: Time course of the incidence of aggravated vertebral fractures, etc.

[0457]

[0458] 2.5. Clinical incidence of vertebral fractures:

[0459] The temporal changes of the clinical vertebral fracture incidence rate based on the Kaplan-Meier method among the analysis subjects of effectiveness are shown in the following Table 2-17.

[0460] [Table 2-17]

[0461] Table 2-17: Changes in the incidence of clinical vertebral fractures over time

[0462]

[0463] Based on the above vertebral fracture incidence data, it can be found that compared with the treatment based on the control drug, the treatment based on the test drug is also superior in terms of overall inhibition of vertebral fractures.

[0464] 2.6. Bone resorption markers:

[0465] The temporal changes of bone resorption markers in the analysis subjects of effectiveness are shown in the following Tables 2-18 to 2-20.

[0466] [Table 2-18]

[0467] Table 2-18: Changes of serum CTX over time

[0468]

[0469] [Table 2-19]

[0470] Table 2-19: Changes of serum NTX over time

[0471]

[0472] [Table 2-20]

[0473] Table 2-20: Time course of NTX in urine

[0474]

[0475] Compared with the time course of the bone resorption marker associated with the treatment with the control drug, the time course of the bone resorption marker associated with the treatment with the test drug is the same as or slightly suppressed ( Figures 5 to 7 ).

[0476] Non-patent document 17 reports that the continuous administration of the test drug causes bone resorption markers to be hyperactive. In addition, in non-patent document 27, erosion surfaces showing bone resorption were confirmed on the surface of the voids of the cortical bone produced by the continuous administration of the test drug (see Fig. 7c, etc.), thus suggesting that the porosity of the cortical bone is closely related to the hyperactivity of bone resorption. Based on the contents of these documents, it is speculated that the time lapse of bone resorption markers in the twice-weekly administration treatment here suggests that the twice-weekly administration treatment is a treatment that is less likely to show hyperactivity of bone metabolism conversion such as an increase in the porosity of the cortical bone than the once-weekly administration treatment.

[0477] 2.7. Bone formation markers:

[0478] The temporal changes of bone formation markers in the analysis subjects of effectiveness are shown in the following Tables 2-21 and 2-22.

[0479] [Table 2-21]

[0480] Table 2-21: Changes of serum OC over time

[0481]

[0482] *: Wilcoxon rank sum test p<0.05

[0483] **: Wilcoxon rank sum test p<0.01

[0484] [Table 2-22]

[0485] Table 2-22: Changes of serum P1NP over time

[0486]

[0487] *: Wilcoxon rank sum test p<0.05

[0488] **: Wilcoxon rank sum test p<0.01

[0489] Compared with the temporal change of bone formation markers associated with treatment with the control drug, the temporal change of bone formation markers associated with treatment with the test drug was higher ( Figures 8-9 ). Particularly in the early stage after the start of administration (herein, from the start of administration to about 12 weeks later), compared with the once-weekly administration, the twice-weekly administration significantly improves the rate of change of bone formation markers. That is, it can be investigated as excellent hyperosteogeny of bone formation, and it can be considered that the twice-weekly administration shows a greater possibility of bone density increase rate than the once-weekly administration.

[0490] 2.8. Security:

[0491] The subjects of safety analysis were defined as subjects who received at least one dose of the test drug or control drug during the treatment period, and the following aggregate analysis was performed. Treatment-emergent adverse events (TEAEs) are adverse events that occur during the treatment period.

[0492] 2.8.1. Adverse events and side effects (summary):

[0493] [Table 2-23]

[0494] Table 2-23: Adverse events and side effects

[0495]

[0496] Compared with the side effect rate based on the administration of the control drug, the side effect rate based on the administration of the test drug was significantly reduced.

[0497] [Table 2-24]

[0498] Table 2-24: Presentation rate of TEAE-related adverse events and side effects

[0499]

[0500] *: p<0.01

[0501] The side effect manifestation rate was divided into three categories: the side effect manifestation rate of TEAE, the side effect manifestation rate of serious adverse events, and the side effect manifestation rate of other important adverse events for analysis. The results showed that in any side effect manifestation rate, the side effect manifestation rate based on the administration of the test drug was significantly lower than the side effect manifestation rate based on the administration of the control drug. Here, important adverse events are defined as adverse events that are serious or lead to discontinuation. In addition, adverse events that remove "serious adverse events" from "important adverse events" are regarded as "other important adverse events."

[0502] 2.8.2. Adverse events and side effects with relatively high incidence (nausea, vomiting, etc.):

[0503] [Table 2-25]

[0504] Table 2-25: The incidence of adverse events and side effects such as nausea and vomiting with relatively high incidence

[0505]

[0506] *: p<0.05, **: p<0.01

[0507] The incidence of adverse events and side effects such as nausea and vomiting, which were common in both groups, tended to be lower in the test drug group than in the control drug group. In addition, the incidence of adverse events and side effects such as "headache" and "fever" also tended to be lower in the test drug group than in the control drug group.

[0508] 2.8.3. Prevalence of adverse events and side effects by organ (neurological disorders, etc.):

[0509] [Table 2-26]

[0510] Table 2-26: Prevalence of adverse events and side effects related to nervous system disorders by organ

[0511]

[0512] Adverse events and side effects were analyzed by organ, and the results showed that the incidence of adverse events and side effects in the test drug group tended to be lower than that in the control drug group in any of the disorders or conditions including nervous system disorders, gastrointestinal disorders, general / systemic disorders, conditions at the administration site, cardiac disorders, and vascular disorders.

[0513] 2.8.4. Rate of adverse events and side effects (shock, hypotension, loss of consciousness) and duration of blood pressure changes Time changes:

[0514] [Table 2-27]

[0515] Table 2-27: Prevalence of adverse events and side effects related to shock

[0516]

[0517] As described above, it is also known that PTH preparations for daily administration and once-weekly administration may cause shock, loss of consciousness accompanied by a temporary and rapid drop in blood pressure, convulsions, and collapse from immediately after administration to several hours later (Non-Patent Documents 4 and 8).

[0518] Here, for events related to blood pressure reduction, the incidence of adverse events and side effects in the test drug group showed a tendency to be lower than that in the control drug group. In addition, for events related to shock and loss of consciousness, no adverse events and side effects were confirmed in the test drug group, showing excellent safety.

[0519] [Table 2-28]

[0520] Table 2-28: Changes in systolic blood pressure after administration relative to before administration over time

[0521]

[0522] In the test drug group, the average value of the systolic blood pressure change (post-drug value - pre-drug value) showed the same downward trend at any test period (0, 4, 12, 24, and 48 weeks later). On the other hand, the average value in the control drug group decreased more significantly after 0, 4, and 12 weeks than in the test drug group. Regarding the degree of blood pressure reduction, the test drug group was -6.3 to -9.4 mmHg, and the control drug group was -7.4 to -12.2 mmHg. The blood pressure reduction in the test drug group was more moderate than that in the control drug group.

[0523] [Table 2-29]

[0524] Table 2-29: Changes in diastolic blood pressure after drug administration relative to before drug administration over time

[0525]

[0526] In the test drug group, the average value of the diastolic blood pressure change (post-drug value - pre-drug value) showed the same downward trend at any test period (0, 4, 12, 24, and 48 weeks). On the other hand, in the control drug group, the decrease in the average value increased after 0, 4, and 12 weeks. Regarding the degree of blood pressure reduction, the test drug group was -4.2 to -6.3 mmHg, and the control drug group was -4.3 to -8.0 mmHg. The blood pressure reduction in the test drug group was more moderate than that in the control drug group.

[0527] 2.8.5. Prevalence of adverse events and side effects by age:

[0528] [Table 2-30]

[0529] Table 2-30: Prevalence of adverse events and side effects by age

[0530]

[0531] The tendency of a decrease in the frequency of side effects due to aging was more significantly observed in the test drug group, and in particular, the frequency of side effects was significantly reduced in patients in the test drug group who were 80 years old or older.

[0532] 2.8.6. Prevalence of adverse events and side effects by gender:

[0533] [Table 2-31]

[0534] Table 2-31: Prevalence of adverse events and side effects by gender

[0535]

[0536] Compared with the control drug group, the test drug group showed excellent safety in both men and women, especially in men, the rate of side effects was significantly reduced.

[0537] 2.8.7. Treatment Continuity:

[0538] [Table 2-32]

[0539] Table 2-32: Treatment persistence

[0540]

[0541] Treatment persistence showed a tendency to be higher in the test drug group than in the control drug group.

[0542] [Table 2-33]

[0543] Table 2-33: Reasons for discontinuation of treatment

[0544]

[0545] The proportion of treatment discontinuation due to adverse events was lower in the test drug group than in the control drug group. In addition, the number of discontinuation due to adverse events within 24 weeks was 25 in the control drug group and 11 in the test drug group. In the test drug group, the number of discontinuation due to adverse events was low, especially in the early stage of treatment.

[0546] [Table 2-34]

[0547] Table 2-34: Details of adverse events leading to treatment discontinuation

[0548]

[0549] (only if there are more than 3 events in any group)

[0550] Compared with the treatment with the control drug group, the treatment with the test drug group was confirmed to improve the treatment persistence by reducing the incidence of adverse events or side effects such as nausea and vomiting.

[0551] 2.9. Analysis of the impact of dosing interval on treatment effect:

[0552] 2.9.1. Analytical methods:

[0553] 242 subjects who completed 48 weeks of treatment in the test drug group (hereinafter referred to as the treatment-completed test drug group) were used as subjects. For each subject, the proportion (%) of weeks in which the dosing interval within a week (excluding the dosing day) was every 2 days and every 3 days in the 48 weeks as the number of weeks during the entire dosing period was calculated (hereinafter referred to as the proportion of complying with the 2-3 day dosing interval). At this time, for weeks that meet the following conditions (1) or (2), it is considered that it does not meet the week in which the dosing interval within a week (excluding the dosing day) is every 2 days and every 3 days.

[0554] (1) The week when the period from the day of administration of the control drug placebo to the day of the next administration of the control drug placebo is within 6 days.

[0555] [Table 2-35]

[0556] Table 2-35: Example of a 5-day period from the day of administration of the control drug placebo to the day of the next control drug placebo administration (Days 1 to 7 in the following table correspond to the week)

[0557]

[0558] (2) When the period from the day of control drug placebo administration to the next control drug placebo administration is 7 days or more, the week in which the test drug is administered at no dosing interval, 1-day dosing interval, 4-day dosing interval, or 5-day dosing interval.

[0559] [Table 2-36]

[0560] Table 2-36: Example of the week when the period from the control drug placebo administration date to the next control drug placebo administration date is 7 days or more and there is no dosing interval for the test drug (Days 1 to 7 in the following table correspond to this week)

[0561]

[0562] [Table 2-37]

[0563] Table 2-37: Example of the week when the period from the control drug placebo administration date to the next control drug placebo administration date is 7 days or more and the test drug is administered at a dosing interval of 1 day (the 1st to 7th days in the following table correspond to the week)

[0564]

[0565] [Table 2-38]

[0566] Table 2-38: Example of the week when the period from the control drug placebo administration date to the next control drug placebo administration date is 7 days or more and the test drug is administered at a dosing interval of 4 days (Days 1 to 7 in the following table correspond to this week)

[0567]

[0568] [Table 2-39]

[0569] Table 2-39: Example of the week when the period from the control drug placebo administration date to the next control drug placebo administration date is 7 days or more and the test drug is administered at a dosing interval of 5 days (Days 1 to 7 in the following table correspond to this week)

[0570]

[0571] After defining the proportion of adherence to the 2- to 3-day dosing interval as described above, the following five types of summary analyses were performed.

[0572] (1) Comparative analysis of the efficacy and safety of the test drug group with a treatment completion rate of more than 70% and a treatment completion rate of less than 70% for the test drug group.

[0573] (2) Comparative analysis of the efficacy and safety of the test drug group in which the proportion of patients adhering to the 2-3 day dosing interval was more than 75% and the treatment completion group in which the proportion of patients adhering to the 2-3 day dosing interval was less than 75%.

[0574] (3) Comparative analysis of the efficacy and safety of the test drug group with a treatment completion rate of 80% or more in compliance with the 2-3 day dosing interval and the test drug group with a treatment completion rate of less than 80% in compliance with the 2-3 day dosing interval.

[0575] (4) Comparative analysis of the efficacy and safety of the test drug group with a treatment completion rate of more than 85% and a treatment completion rate of less than 85% for the test drug group.

[0576] (5) Comparative analysis of the effectiveness and safety of the test drug group in which the proportion of patients adhering to the 2-3 day dosing interval was more than 90% and the treatment completion group in which the proportion of patients adhering to the 2-3 day dosing interval was less than 90%.

[0577] Here, the evaluation items for effectiveness are the change rate of lumbar vertebrae bone density (2nd to 4th lumbar vertebrae), the change rate of femoral neck bone density, the change rate of proximal femoral bone density (proximal femoral whole), clinical fracture incidence rate and non-vertebral fracture incidence rate. In addition, the evaluation items for safety are the total side effect expression rate and nausea (side effect) expression rate.

[0578] In addition, the average number of administration times and the average number of administration periods in each group for comparison were calculated.

[0579] 2.9.2.Analysis results:

[0580] 2.9.2.1. Average number of doses and average duration of doses:

[0581] The average number of dosing times and average dosing duration were calculated for each dosing interval compliance ratio using 242 subjects in the test drug group who had completed treatment. The results are shown in the following Table 2-40.

[0582] [Table 2-40]

[0583] Table 2-40: Average number of dosing times and average dosing duration (days) for each proportion of adherence to a 2- to 3-day dosing interval, divided by a specific value or less

[0584]

[0585] In the comparison of the two cases where the proportion of compliance with the 2-3 day dosing interval was 70% or more and the proportion was less than 70%, there was no significant difference in the average number of dosing times and the average dosing period, and they were at the same level. In addition, when the values ​​of 75%, 80%, 85%, and 90% for the compliance with the 2-3 day dosing interval were compared to the values ​​above the specific value and below the specific value, the same results were obtained as when the proportion of compliance with the 2-3 day dosing interval was 70% or more. Therefore, even for different proportions of compliance with the 2-3 day dosing interval, there was no difference in the average number of dosing times and the average dosing period, and it can be considered that there was no difference in the exposure amount of the clinical trial drug.

[0586] 2.9.2.2. For each type of percentage of patients who adhere to a 2- to 3-day dosing interval, the percentage of patients who adhere to a 2- to 3-day dosing interval is divided into those who are above or below a specific value. The average value of the change rate of bone density of the lumbar spine, femoral neck and proximal femoral part under different conditions (%):

[0587] The average value (%) of the change in bone density of the lumbar spine, femoral neck, and proximal femoral region was calculated when the proportion of adherence to the 2- to 3-day dosing interval was classified as above / below a specific value. The results are shown in the following Tables 2-41 to 2-43.

[0588] [Table 2-41]

[0589] Table 2-41: Average value (%) of change rate of lumbar vertebrae bone density (2nd to 4th lumbar vertebrae) when the proportion of compliance with 2-3 day dosing interval is classified as above / below a specific value

[0590]

[0591] [Table 2-42]

[0592] Table 2-42: Average value (%) of the change rate of bone density at the femoral neck when the proportion of compliance with the 2- to 3-day dosing interval was classified as above / below the specific value

[0593]

[0594] [Table 2-43]

[0595] Table 2-43: Average value (%) of change in bone density of the entire proximal femur when the proportion of compliance with the 2- to 3-day dosing interval was classified as above / below a specific value

[0596]

[0597] In addition, the changes in the mean values ​​(%) of the lumbar spine bone density (2nd to 4th lumbar vertebrae), the femoral neck bone density, and the proximal femoral bone density were compared with the specific values ​​and the specific values ​​for each proportion of the 2-3 day dosing interval, and the curves were shown in the graph. Figures 10 to 24 .

[0598] As mentioned above, lumbar bone density (2nd to 4th lumbar vertebrae) is the main evaluation item for the effectiveness of this test. Therefore, the influence of the change of the specific value on the average value (%) of the change rate of lumbar bone density (2nd to 4th lumbar vertebrae) shown by patients whose proportion of 2-3 day dosing intervals is above a certain specific value (%) at the time of 48 weeks after the start of administration was analyzed and the results are shown in Fig.25 .

[0599] In the layer where the proportion of complying with the 2-3 day dosing interval is above a specific value, as the proportion of complying with the 2-3 day dosing interval increases, the average value (%) of the bone density change rate tends to increase. Therefore, it is believed that the higher the proportion of weeks in which the dosing interval (excluding the dosing day) within a week is every 2 days and every 3 days, the higher the therapeutic effect can be obtained. More specifically, a good therapeutic effect is shown in a method where the ratio is 70% or more, and a more significant therapeutic effect can be obtained in a method where the ratio is 90% or more. In addition, considering the strong positive correlation between the ratio and the therapeutic effect, it is considered that by making the ratio 100%, the therapeutic effect can be maximized.

[0600] On the other hand, the compliance rate of 2-3 days dosing interval (including the dosing day, every 3 days, 4 days) was 0%, and there were 2 cases of administration twice a week with an interval of about 1 day and 4 days (including the dosing day, every 2 days, 5 days). The average value (%) of the change rate of lumbar bone density (2nd to 4th lumbar vertebrae) of these 2 cases was analyzed, and the result was 5.8% and 5.9% in one case 48 weeks after the start of administration. The inventor believes that this result also suggests that it is useful to comply with the 2-3 days dosing interval (including the dosing day, every 3 days, 4 days) when administering twice a week.

[0601] 2.9.2.3. When the proportion of compliance with the 2-3 day dosing interval is 75-85% or 85-100%, Average change rate of bone density in different regions (%):

[0602] [Table 2-44]

[0603] Table 2-44: Average value of bone density change rate in each sub-area when the proportion of compliance with the 2-3 day dosing interval is divided into 75-85% and 85-100% (%)

[0604]

[0605] 2.9.2.4. For each type of percentage of patients who adhere to a 2- to 3-day dosing interval, the percentage of patients who adhere to a 2- to 3-day dosing interval is classified as above or below a specific value. The incidence of clinical fractures and non-vertebral fractures in different cases:

[0606] The incidence rates of clinical fractures and non-vertebral fractures were calculated for each of the rates of adherence to the 2- to 3-day dosing intervals, classified as being above or below a specific value. The results are shown in the following Tables 2-45 and 2-46.

[0607] [Table 2-45]

[0608] Table 2-45: Number of cases and fracture incidence ratio (%) of clinical fractures when the proportion of compliance with the 2-3 day dosing interval was classified as above / below a specific value

[0609]

[0610] [Table 2-46]

[0611] Table 2-46: Number of non-vertebral fractures and fracture incidence ratio (%) for each 2-3 day dosing interval compliance ratio classified as above / below a specific value

[0612]

[0613] As described above, clinical fractures are fractures of both vertebral and non-vertebral types. Therefore, the effect of changes in specific values ​​on the incidence rate (%) of clinical fractures shown by patients whose proportion of compliance with the 2-3 day dosing interval is above a certain specific value (%) was analyzed and the results are shown in Fig.26 .

[0614] In the layer above the specific value, as the proportion of complying with the 2-3 day dosing interval increases, the fracture occurrence ratio (%) tends to decrease basically. Therefore, it is believed that the higher the proportion of the week in which the dosing interval (excluding the dosing day) within a week is 2 days and 3 days, the higher the therapeutic effect can be obtained. More specifically, the ratio shows a good therapeutic effect in the mode of more than 70%, and furthermore, a more significant therapeutic effect can be obtained in the mode of more than 90%. In addition, considering the strong positive correlation between the ratio and the therapeutic effect, it is investigated that by making the ratio 100%, the therapeutic effect can be maximized.

[0615] 2.9.2.5. When the compliance rate for each dosing interval is classified as above or below a specific value The following bone metabolism markers (urinary NTX (u-NTX), serum NTX (s-NTX), CTX, OC, P1NP) over time:

[0616] The temporal changes of bone metabolism markers (urinary NTX (u-NTX), serum NTX (s-NTX), CTX, OC, and P1NP) were calculated for each dosing interval compliance ratio when the ratio was classified as above / below a specific value. The results are shown in Tables 2-47 to 2-51 below.

[0617] [Table 2-47]

[0618] Table 2-47: Median value (%) of the change rate of urinary NTX (u-NTX) at each time point when the ratio of compliance with the 2- to 3-day dosing interval was classified as above / below a specific value

[0619]

[0620] [Table 2-48]

[0621] Table 2-48: Median value (%) of the change rate of serum NTX (s-NTX) at each time point when the proportion of compliance with the 2- to 3-day dosing interval was classified as above / below a specific value

[0622]

[0623] [Table 2-49]

[0624] Table 2-49: Median value of the change rate of CTX at each time point when the proportion of compliance with the 2- to 3-day dosing interval is classified as above / below a specific value (%)

[0625]

[0626] [Table 2-50]

[0627] Table 2-50: Median value of the change rate of OC at each time point when the proportion of compliance with the 2- to 3-day dosing interval was classified as above / below a specific value (%)

[0628]

[0629] [Table 2-51]

[0630] Table 2-51: Median value of the change rate of P1NP at each time when the compliance rate of each dosing interval is classified as above / below a specific value (%)

[0631]

[0632] As a bone metabolism marker for observing the bone formation effect of a preparation for daily administration and a preparation for once-weekly administration containing teriparatide or its salt as an active ingredient, osteocalcin (OC) in serum is widely used (Non-patent Document 5, etc.). In addition, in the test drug administration of the present invention, a peak of OC increase was confirmed about 4 weeks after the start of administration ( Figure 8 ). Therefore, the influence of the change of the specific value on the OC shown by the patients whose proportion of the dosing interval of 2 to 3 days after the start of the administration is more than a certain specific value (%) was analyzed and the results are shown in Fig. 27 .

[0633] Regarding OC, a bone formation marker, unlike the above-mentioned treatment effect, no clear correlation was found with the proportion of adherence to the 2- to 3-day dosing interval in the layer with a value greater than or equal to a specific value.

[0634] Parathyroid hormone is known to be a bone formation promoter (Non-Patent Document 9), and the deviation of bone formation markers and bone resorption markers is understood to be an indicator of effectiveness in the treatment of osteoporosis using teriparatide for several days (Non-Patent Document 24). Therefore, regarding the correlation with the proportion of compliance with the 2-3 day dosing interval, the treatment effect and OC, which is a bone formation marker, showed different trends, and compared with the existing technical ideas of teriparatide therapy, this analysis result is considered to be extremely groundbreaking.

[0635] 2.9.2.6. When the compliance rate for each dosing interval is classified as above or below a specific value The number and proportion (%) of all side effects and nausea (side effect) as follows:

[0636] [Table 2-52]

[0637] Table 2-52: Number of cases and occurrence ratio (%) of all side effects when the proportion of compliance with the 2-3 day dosing interval is classified as above / below a specific value

[0638]

[0639] [Table 2-53]

[0640] Table 2-53: Number of cases and occurrence ratio (%) of nausea (side effect) when the proportion of compliance with the 2-3 day dosing interval is classified as above / below a specific value

[0641]

[0642] As mentioned above (2.8.2), nausea is the side effect with the highest occurrence rate. Therefore, the influence of the change of the specific value on the occurrence rate (%) of nausea in patients whose proportion of patients who adhere to the dosing interval of 2 to 3 days is above a certain specific value (%) is analyzed and the results are shown in Fig.28 .

[0643] In the group where the dosing interval compliance ratio is above a specific value, the occurrence ratio of nausea (side effect) tends to decrease as the dosing interval compliance ratio increases. Therefore, it is believed that the higher the proportion of weeks in which the dosing interval (excluding the dosing day) within a week is every 2 days and 3 days, the safer the treatment is. More specifically, good safety is shown in the mode where the ratio is 70% or more. Considering the tendency of a strong positive correlation between the ratio and safety, it is considered that by making the ratio 100%, safety can be maximized.

[0644] (Example 2)

[0645] 1. Test methods

[0646] For female rabbits aged 6 months, teriparatide was administered subcutaneously at a weekly dose of 140 μg / kg once a week, twice a week or 7 times a week for 4 weeks, or a control drug without teriparatide was administered subcutaneously 7 times a week for 4 weeks to study the effects on bone metabolism and bone tissue structure (Table 2-54). Tibia bone density and bone strength were also measured. The teriparatide solution to be administered was prepared by dissolving teriparatide acetate in water for injection, filtering and filling in a vial, freeze-drying, and dissolving the resulting preparation in a physiological saline solution when used.

[0647] [Table 2-54]

[0648] Table 2-54: Contents of each test group

[0649]

[0650] 2. Test results

[0651] (1) Tibial bone density

[0652] The tibia bone density was analyzed by segmentation area, and the result showed that compared with the control group, this drug significantly increased the bone density of the proximal part (1 / 5 part) with more spongy bone, and the bone density of the twice-weekly administration group in this part was higher than that of the once-weekly administration group. This test result is consistent with the following test results (Table 2-4) of Example 1: in the lumbar vertebrae (2nd to 4th lumbar vertebrae) with more spongy bone as the proximal part of the tibia (60% of the lumbar vertebrae are spongy bone, and 80% of the vertebral body are spongy bone; Non-patent literature 26), the bone density of the twice-weekly administration group showed a higher value than that of the once-weekly administration group.

[0653] [Table 2-55]

[0654] Table 2-55: Effect of teriparatide administration frequency on bone density in the proximal tibia (1 / 5) of rabbits

[0655] Control group Once a week dosing group Twice weekly dosing group <![CDATA[Bone density (mg / cm 2 )]]> 254.2±10.9 272.5±13.6 278.8±9.8

[0656] (2) Tibial bone strength

[0657] The three-point bending bone strength of the tibia collected after the end of the administration was measured. As a result, the maximum load showed a higher value in the group where the drug was administered twice a week and the group where the drug was administered seven times a week than in the control group.

[0658] [Table 2-56]

[0659] Table 2-56: Effect of teriparatide administration frequency on rabbit tibia bone strength

[0660]

[0661] (3) Bone tissue morphology of the tibial diaphysis

[0662] In the 7-times-a-week dosing group, spongiositization of the cortical bone endometrial surface, numerous voids (porosis) within the cortical bone, and disordered lamella structure were observed, whereas none of these events were observed in the 1-times-a-week and 2-times-a-week dosing groups.

[0663] It is reported that non-patent document 14 suggests that high-frequency administration of teriparatide promotes bone metabolic transformation and that the increase in cortical bone void ratio caused by teriparatide is strongly affected by the frequency of administration. In this example, although the administration frequency was doubled compared to the once-weekly administration treatment, the twice-weekly administration treatment did not confirm the promotion of bone metabolic transformation such as the increase in cortical bone void ratio, which is considered to be an unexpected and groundbreaking result compared to non-patent document 14.

[0664] In addition, Non-Patent Document 17 reports that continuous administration of the test drug causes bone resorption markers to increase. In Non-Patent Document 27, erosion surfaces showing bone resorption were confirmed on the surface of the voids in the cortical bone generated by continuous administration of the test drug (see Fig. 7c, etc.), suggesting that the porosity of the cortical bone is closely related to the increase in bone resorption.

[0665] In Example 1, the time course of the bone resorption markers accompanying the treatment with twice-weekly dosing was the same as or slightly suppressed compared to the time course of the bone resorption markers accompanying the treatment with once-weekly dosing ( Figures 5 to 7 ), it can be inferred from such a mechanism that the twice-weekly dosing treatment is a treatment that does not show hyperactivity of bone metabolism such as increasing the porosity of cortical bone, despite dosing frequency being doubled compared to the once-weekly dosing treatment. Therefore, the effect in Example 1 can be supported by the experimental results in rabbits in Example 2.

Claims

1. Use of teriparatide or a salt thereof in the preparation of an agent for treating and / or preventing osteoporosis, wherein the agent contains 28.2 μg of teriparatide or a salt thereof so that the amount of teriparatide or a salt thereof is administered twice a week.

2. The use according to claim 1, wherein: The intervals between two doses in a week are 2 days and 3 days, and the dose day is not included in the interval between doses.

3. The use according to claim 1, wherein: When n is the number of weeks during which the drug is administered twice a week and m is the number of weeks during which the intervals between two administrations are 2 days and 3 days, (m / n)×100(%) is 70% or more, and the number of days between administrations does not include the administration day.

4. The use according to any one of claims 1 to 3, which is administered subcutaneously.

5. An agent for treating and / or preventing osteoporosis, comprising teriparatide or a salt thereof as an active ingredient, and is administered to a patient having a lumbar spine bone density of less than 60% of the average value of young adults.

6. The therapeutic and / or preventive agent for osteoporosis according to claim 5, wherein: 28.2 μg of teriparatide or a salt thereof was administered twice a week.

7. An agent for treating and / or preventing osteoporosis, comprising teriparatide or a salt thereof as an active ingredient, and is administered to a patient who has previously suffered one vertebral fracture.

8. The therapeutic and / or preventive agent for osteoporosis according to claim 7, wherein: 28.2 μg of teriparatide or a salt thereof was administered twice a week.

9. An agent for treating and / or preventing osteoporosis, comprising teriparatide or a salt thereof as an active ingredient, and is administered to a patient having a serum osteocalcin concentration of less than 15.2 (ng / mL).

10. The therapeutic and / or preventive agent for osteoporosis according to claim 9, wherein: 28.2 μg of teriparatide or a salt thereof was administered twice a week.

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