WO2020090174A1 - 週2回の頻度でテリパラチド又はその塩を投与することを特徴とする、骨粗鬆症の予防又は治療方法 - Google Patents
週2回の頻度でテリパラチド又はその塩を投与することを特徴とする、骨粗鬆症の予防又は治療方法 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Definitions
- the present invention relates to a method for preventing or treating osteoporosis, which comprises administering teriparatide or a salt thereof twice a week.
- Osteoporosis is defined as "a skeletal disease characterized by a decrease in bone strength and increasing the risk of fracture" (Non-Patent Document 1), and this definition is commonly used.
- the main purpose of prevention and treatment of osteoporosis is to prevent or suppress bone fractures and maintain life function and quality of life (QOL). Since the pain due to bone fracture, the deterioration of body support function, and the subsequent life dysfunction due to motor dysfunction are serious problems, it can be said that the prevention and treatment of osteoporosis, which has a high risk of bone fracture, has a high clinical significance.
- Non-patent Documents 4 and 8 a drug for daily administration or a once-weekly drug containing teriparatide or a salt thereof as an active ingredient has been developed as a drug for treating osteoporosis, which has a high risk of fracture, and has been approved for marketing. After that, it is actually used in clinical practice (Non-patent Documents 4 and 8).
- a daily administration preparation or a once-weekly administration preparation containing teriparatide or a salt thereof as an active ingredient is not always sufficiently excellent in terms of safety.
- Non-Patent Document 21 It is known that PTH has a vascular smooth muscle relaxing action (Non-Patent Document 21). In clinical trials in which a formulation for daily administration was provided, dizziness was reported to be significantly higher than that in the placebo group (Non-Patent Document 9). It is also known that shock, loss of consciousness accompanied by transient and sudden drop in blood pressure, convulsions, and falls may occur immediately after the administration of the daily administration preparation or the once-weekly administration preparation, and several hours later. (Non-patent documents 4 and 8).
- Non-Patent Document 9 it has been reported that administration of teriparatide acetate often causes nausea, vomiting, headache, etc.
- the frequency of nausea was significantly higher than that of the placebo group, and the numerical value also exceeded 20% of the once-weekly formulation group. It has also been reported that the discontinuation rate showed a high value of about 20% (Non-Patent Document 5).
- Non-Patent Document 9 As factors associated with poor compliance, the presence of pain, side effects, medication for gastrointestinal disorders, etc. are exemplified (Non-Patent Document 9).
- Non-Patent Document 23 Regarding safety, it is known that adverse drug reactions may be reduced due to side effects, and in the study in which the once-weekly formulation was provided, adverse events leading to the discontinuation of study drug other than serious It is reported as high as 14.1% (Non-Patent Document 23).
- the daily administration formulation and the once-weekly administration formulation containing teriparatide or a salt thereof as active ingredients show many problems in terms of safety, but provide sufficient benefits in terms of efficacy. It cannot always be said that they are doing it.
- Non-Patent Document 6 In addition, in a clinical study in which the administration period is 72 weeks when a once-weekly formulation is provided to an osteoporosis patient with a high risk of fracture, the lumbar spine bone density is 4.9 to 6. It has been reported to increase by about 0% (Patent Document 1 (Table 26), Non-Patent Document 5 (FIG. 3)). In addition, in a clinical study in which the once-weekly administration preparation was given to an osteoporosis patient with a high risk of fracture for a 24-month administration period, the lumbar bone density increased by about 6.9% at 48 weeks after the start of administration. It has been reported to do so (Non-Patent Document 6).
- Non-Patent Document 7 the effect of increasing bone density but also the effect of inhibiting bone fracture are known. For example, it has been reported that the risk of vertebral body fracture is reduced by 65% in a clinical test in which a formulation for daily administration is provided (Non-Patent Document 7).
- teriparatide has a strong osteogenesis promoting action in sites with many cancellous bones such as vertebral bodies
- the action on cortical bone may be different depending on the administration frequency even in the intermittent administration of PTH (Non-patent Document 14).
- CTX which is one of the bone resorption markers, tends to increase in a dose-dependent manner at 24 weeks after the start of daily administration of teriparatide, compared with the start of administration).
- Non-patent Document 14 From studies in ovariectomized rats, which are widely used as osteoporosis models, it has been reported that bone density and bone strength increase according to the dose of teriparatide per week (Non-patent Document 14).
- An object of the present invention is to provide a method for treating and / or preventing osteoporosis with teriparatide or a salt thereof, which is excellent in safety and / or efficacy, and a therapeutic and / or preventive agent for osteoporosis containing teriparatide or a salt thereof as an active ingredient. Is to provide.
- One embodiment of the therapeutic and / or prophylactic agent for osteoporosis and the method for treating and / or preventing osteoporosis of the present invention comprises teriparatide or a salt thereof as an active ingredient, and 28.2 ⁇ g of teriparatide or a salt thereof is administered twice a week. It is characterized in that it is administered in.
- the therapeutic and / or prophylactic agent for osteoporosis and the method for treating and / or preventing osteoporosis show excellent safety and / or efficacy.
- the present invention relates to the following inventions.
- n be the number of weeks in which the drug is administered twice a week, and the interval between two administrations within the n weeks is 2 days and 3 days (dosing days are not included).
- the therapeutic and / or prophylactic agent for osteoporosis according to any of the above [1] to [4] which is administered to a person aged 80 years or older.
- the therapeutic and / or prophylactic agent for osteoporosis according to any one of the above [1] to [4], which is administered to an osteoporotic patient who satisfies the following conditions (1) to (3): (1) Age is 65 years or older; (2) The number of existing vertebral body fractures is 1 or more and 5 or less; (3) The lumbar bone density is less than 80% of the average value of the young adult.
- a therapeutic and / or preventive agent for osteoporosis containing teriparatide or a salt thereof as an active ingredient, which is excellent in safety and / or efficacy, and a therapeutic and / or preventive method for osteoporosis.
- FIG. 1 shows a case where the therapeutic agent for osteoporosis or the like of the present invention is administered twice a week for 2 weeks, and the administration interval is 1 and 6 days (0 and 0 when the administration day is not included). 5 days interval), 2 and 5 days interval (1 and 4 days interval when the administration date is not included), or 3 and 4 days interval (2 and 3 days interval when the administration date is not included) It is a figure which shows the example of an administration plan in case of.
- FIG. 2 shows a case where the therapeutic agent for osteoporosis, etc. of the present invention is administered twice a week for 2 weeks, and the administration interval is 3 and 4 days (2 and It is a figure which shows the example of an administration plan when it is set as every 3 days.
- FIG. 1 shows a case where the therapeutic agent for osteoporosis or the like of the present invention is administered twice a week for 2 weeks, and the administration interval is 1 and 6 days (0 and 0 when the administration day is not included). 5 days interval), 2 and 5 days interval (1 and 4 days interval when
- FIG. 4 is a graph showing changes in the lumbar spine bone density (second to fourth lumbar vertebrae) change rate average values (%) when the therapeutic agent for osteoporosis, etc. of the present invention was administered to osteoporosis patients for 48 weeks.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the average rate of change (%) from the start.
- “BL” indicates Baseline.
- “Final” includes the rate of change (%) in the lumbar spine density (second to fourth lumbar vertebrae) of patients who discontinued treatment during the middle of 48 weeks, including the lumbar bone density (second to fourth lumbar bone density) at the end of treatment for each patient. It means the "end of treatment” to show the rate of change (%) in the lumbar spine.
- the numbers shown in the lower two rows mean the number of patients treated in each week. “**” indicates p ⁇ 0.01.
- FIG. 5 is a graph showing changes in the median change rate (%) of serum CTX when the therapeutic agent for osteoporosis, etc. of the present invention is administered to an osteoporosis patient for 48 weeks.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the median rate of change (%) from the start.
- “BL” indicates Baseline.
- the numbers shown in the bottom two rows refer to the number of patients tested each week.
- FIG. 6 is a graph showing changes in the median change rate (%) of serum NTX when the therapeutic agent for osteoporosis of the present invention or the like is administered to an osteoporosis patient for 48 weeks.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the median rate of change (%) from the start.
- “BL” indicates Baseline. The numbers shown in the bottom two rows refer to the number of patients tested each week.
- FIG. 7 is a graph showing changes in the median change rate (%) of urinary NTX when the therapeutic agent for osteoporosis, etc. of the present invention is administered to an osteoporosis patient for 48 weeks.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the median rate of change (%) from the start.
- “BL” indicates Baseline.
- the numbers shown in the bottom two rows refer to the number of patients tested each week.
- FIG. 8 is a graph showing changes in the median change rate (%) of serum OC (osteocalcin) when the therapeutic agent for osteoporosis, etc. of the present invention is administered to an osteoporosis patient for 48 weeks.
- FIG. 9 is a graph showing changes in the median change rate (%) of serum P1NP when the therapeutic agent for osteoporosis, etc. of the present invention is administered to an osteoporosis patient for 48 weeks.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the median rate of change (%) from the start.
- BL indicates Baseline.
- FIG. 10 shows changes in the lumbar vertebra bone density (second to fourth lumbar vertebrae) change rate average values (%) when the therapeutic agent for osteoporosis, etc. of the present invention was administered to osteoporosis patients for 48 weeks, and the administration interval compliance rate was 70%. It is the figure classified by% or more and less than 70%.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the average rate of change (%) from the start.
- the numerical values shown in the lower two rows mean the number of patients to be analyzed in each week.
- FIG. 11 shows changes in the lumbar vertebra bone density (second to fourth lumbar vertebrae) change rate average values (%) when the therapeutic agent for osteoporosis, etc. of the present invention was administered to osteoporosis patients for 48 weeks. It is the figure classified by% or more and less than 75%.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the average rate of change (%) from the start.
- the numerical values shown in the lower two rows mean the number of patients to be analyzed in each week.
- FIG. 12 shows changes in the lumbar vertebra bone density (second to fourth lumbar vertebrae) changes in mean value (%) when the therapeutic agent for osteoporosis, etc. of the present invention was administered to osteoporosis patients for 48 weeks.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the average rate of change (%) from the start.
- the numerical values shown in the lower two rows mean the number of patients to be analyzed in each week.
- FIG. 13 shows changes in the lumbar vertebra bone density (second to fourth lumbar vertebrae) change rate average values (%) when the therapeutic agent for osteoporosis, etc. of the present invention was administered to osteoporosis patients for 48 weeks. It is the figure classified by% or more and less than 85%.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the average rate of change (%) from the start.
- the numerical values shown in the lower two rows mean the number of patients to be analyzed in each week.
- FIG. 14 shows changes in the lumbar vertebra bone density (second to fourth lumbar vertebrae) changes in mean value (%) when the therapeutic agent for osteoporosis, etc. of the present invention was administered to osteoporosis patients for 48 weeks, and the administration interval compliance rate was 90%. It is the figure classified by% or more and less than 90%.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the average rate of change (%) from the start.
- the numerical values shown in the lower two rows mean the number of patients to be analyzed in each week.
- FIG. 15 shows changes in the average change rate (%) of femoral neck bone density when the therapeutic agent for osteoporosis, etc.
- FIG. 16 shows changes in the average rate of change (%) in femoral neck bone density when the therapeutic agent for osteoporosis, etc. of the present invention was administered to osteoporosis patients for 48 weeks, the administration interval compliance rate was 75% or more, 75% It is the figure classified by less than.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the average rate of change (%) from the start.
- the numerical values shown in the lower two rows mean the number of patients to be analyzed in each week.
- FIG. 17 shows changes in the average change rate (%) of femoral neck bone density when the therapeutic agent for osteoporosis, etc. of the present invention was administered to an osteoporosis patient for 48 weeks, the administration interval compliance rate being 80% or more, 80% It is the figure classified by less than.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the average rate of change (%) from the start.
- the numerical values shown in the lower two rows mean the number of patients to be analyzed in each week.
- FIG. 18 shows changes in the average change rate (%) of femoral neck bone density when the therapeutic agent for osteoporosis, etc. of the present invention was administered to an osteoporosis patient for 48 weeks, and the administration interval compliance rate was 85% or more, 85%. It is the figure classified by less than.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the average rate of change (%) from the start.
- the numerical values shown in the lower two rows mean the number of patients to be analyzed in each week.
- FIG. 19 shows changes in the average change rate (%) of femoral neck bone density when the therapeutic agent for osteoporosis, etc.
- FIG. 20 shows changes in the average rate of change (%) in the total bone density of the proximal femur when the therapeutic agent for osteoporosis or the like of the present invention was administered to an osteoporosis patient for 48 weeks. It is the figure classified by less than 70%.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the average rate of change (%) from the start.
- the numerical values shown in the lower two rows mean the number of patients to be analyzed in each week.
- FIG. 21 shows changes in the average change rate (%) of the total bone density of the proximal femur when the therapeutic agent for osteoporosis, etc. of the present invention was administered to an osteoporosis patient for 48 weeks, the administration interval compliance rate was 75% or more, It is the figure classified by less than 75%.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the average rate of change (%) from the start.
- the numerical values shown in the lower two rows mean the number of patients to be analyzed in each week.
- FIG. 22 shows changes in the average rate of change (%) in the total bone density of the proximal femur when the therapeutic agent for osteoporosis or the like of the present invention was administered to an osteoporosis patient for 48 weeks. It is the figure classified by less than 80%.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the average rate of change (%) from the start.
- the numerical values shown in the lower two rows mean the number of patients to be analyzed in each week.
- FIG. 23 shows changes in the average rate of change (%) in the total bone density of the proximal femur when the therapeutic agent for osteoporosis or the like of the present invention was administered to an osteoporosis patient for 48 weeks. It is the figure classified by less than 85%.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the average rate of change (%) from the start.
- the numerical values shown in the lower two rows mean the number of patients to be analyzed in each week.
- FIG. 24 shows changes in the average rate (%) of changes in the total bone density of the proximal femur when the therapeutic agent for osteoporosis, etc. of the present invention was administered to an osteoporosis patient for 48 weeks, the administration interval compliance rate of 90% or more, It is the figure classified by less than 90%.
- the horizontal axis represents the number of weeks of administration, and the vertical axis represents the average rate of change (%) from the start.
- the numerical values shown in the lower two rows mean the number of patients to be analyzed in each week.
- FIG. 25 shows a case where the therapeutic agent for osteoporosis of the present invention or the like was administered to an osteoporosis patient whose compliance rate of the administration interval for each 2-3 days was more than each specific value (70, 75, 80, 85, 90%).
- FIG. 8 is a graph showing the average change rate (%) in the lumbar spine bone density (second to fourth lumbar vertebrae) observed 48 weeks after the start of administration.
- FIG. 26 shows the case where the therapeutic agent for osteoporosis, etc. of the present invention was administered to an osteoporosis patient whose compliance rate of the administration interval for 2 to 3 days each showed a specific compliance value (70, 75, 80, 85, 90%) or more. It is a figure which shows the fracture occurrence rate (%) of clinical fracture.
- FIG. 27 shows the case where the therapeutic agent for osteoporosis or the like of the present invention was administered to an osteoporosis patient whose compliance rate for the administration interval for each 2-3 days was more than the specified value (70, 75, 80, 85, 90%).
- FIG. 8 is a graph showing the median change rate (%) observed 4 weeks after the start of OC administration in 4 weeks.
- FIG. 28 shows a case where the therapeutic agent for osteoporosis, etc. of the present invention was administered to an osteoporosis patient whose compliance rate of the administration interval for each 2-3 days was more than each specific value (70, 75, 80, 85, 90%).
- FIG. 6 is a diagram showing the incidence rate (%) of nausea (side effect) of.
- FIG. 29 shows the basic administration schedule of the test drug group and the control drug group.
- human PTH (1-34) is composed of amino acid residues from the 1st to 34th amino acids as viewed from the N-terminal side in the amino acid sequence of human PTH (1-84), which is a human parathyroid hormone. It is a peptide represented by a partial amino acid sequence.
- teriparatide means human PTH (1-34) in a free form. Teriparatide can also be in salt form.
- the teriparatide salt includes any salt formed by teriparatide and one or more volatile organic acids.
- the volatile organic acid include trifluoroacetic acid, formic acid, acetic acid and the like.
- the ratio of teriparatide in the free form and the volatile organic acid when forming a salt is not particularly limited as long as the salt is formed.
- acetic acid is preferable as the volatile organic acid. That is, as the teriparatide salt in the present invention, teriparatide acetate can be preferably exemplified.
- Teriparatide or a salt thereof can be produced by a method known per se (Patent Documents 1 to 3 etc.).
- the dose of the active ingredient contained in the osteoporosis treatment and / or prevention agent of the present invention and used in the osteoporosis treatment method and / or prevention method of the present invention is not particularly limited, but is preferably Can be exemplified as follows.
- the dose of the active ingredient per dose is more preferably 20 ⁇ g or more, 25 ⁇ g or more, 27 ⁇ g or more, or 28 ⁇ g or more.
- the dose of the active ingredient contained in the therapeutic and / or prophylactic agent for osteoporosis of the present invention is preferably 40 ⁇ g or less, more preferably 35 ⁇ g or less, or more preferably 30 ⁇ g or less.
- the dose of the active ingredient per dose is preferably 28.2 ⁇ g or 29.2 ⁇ g as teriparatide.
- teriparatide used is an acetate
- a dose in which the amount of acetic acid is added can be exemplified.
- the dose of the active ingredient per dose is 30.3 ⁇ g as teriparatide acetate.
- it is preferably 31.3 ⁇ g.
- the dose of teriparatide salt per dose means an amount of 28.2 ⁇ g as teriparatide, and teriparatide acetate In the case, it is 30.3 ⁇ g.
- the osteoporosis treatment and / or prevention agent of the present invention and the osteoporosis treatment method and / or prevention method of the present invention are characterized by being administered twice a week.
- the intervals of administration within a week are 1) 1 and 6 days (0 and 5 days if the administration days are not included). 2) 2 and 5 day intervals (1 and 4 day intervals when the administration date is not included), or 3) 3 and 4 day intervals (2 and 3 day intervals when the administration date is not included) Can be (FIG. 1).
- Intervals of administration within a week are not particularly limited, but an aspect of 3 or 4 day intervals (2 or 3 day intervals when the administration day is not included) is most preferred.
- the intervals of administration within a week are 3 and 4 day intervals (2 and 3 day intervals when the administration day is not included) will be specifically described with reference to an administration schedule example from the initial administration to 2 weeks.
- the administration can be performed twice a week in the week of the first administration (the 1st week), and then on the 8th day, the 11th or 12th day.
- it can be administered twice a week in the second week (FIG. 2).
- the time of administration is not particularly limited, and may be during the day or at night. When the time of administration is daytime, the administration may be in the morning or in the afternoon. However, when other therapeutic agents or basic agents (Ca, vD agents, etc.) are used in combination, it is more preferable that the medication times do not overlap with each other.
- the number of weeks during which the therapeutic agent for osteoporosis or the like of the present invention is administered twice a week is defined as n, and the interval between two administrations within a week is 3 and 4 days (when the administration day is not included, (M / n) ⁇ 100 (%) can be a certain value or more, and the lower limit of the ratio is 50%, 60%, 70%, 75. %, 80%, 85%, 90%, and 95% can be exemplified, and the lower limit of the same ratio is preferably 80% or more, and more preferably 90% or more.
- the interval of administration twice a week is 3 and 4 days (including the administration day). If the number of weeks of 2 and 3 days is 2, the above (m / n) ⁇ 100 is 2 ⁇ (34 ⁇ 7) ⁇ 100, that is, about 41.2 (%). Is calculated.
- the administration route 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 not particularly limited, and it may be administered intravenously, subcutaneously or intramuscularly. Among them, subcutaneous administration can be preferably exemplified.
- 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 may be administered, for example, to the upper arm, thigh, or abdomen. However, in the second administration, it is preferable that the administration is performed at a site separated by at least about 3 cm from the previous administration site. Immediately before the administration, the administration can be facilitated by picking the area around the administration site by hand and raising the administration site and its periphery from the skin surface.
- the administration period 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 not particularly limited, and can be appropriately determined according to the prescription of the doctor in charge according to the patient.
- the lower limit of the administration period is not particularly limited, and the administration period is preferably, for example, 4 weeks or more, 8 weeks or more, 12 weeks or more, 24 weeks or more, 48 weeks or more, or 1 year or more.
- the upper limit of the administration period is not limited, and the upper limit of the administration period can be preferably, for example, within 5 years, within 4 years, within 3 years, or within 2 years.
- (6-1) Disease The agent for treating and / or preventing osteoporosis of the present invention and the method for treating and / or preventing osteoporosis of the present invention are characterized by being administered for the purpose of treating and / or preventing osteoporosis.
- the osteoporosis according to the present invention means "a skeletal disease characterized by a decrease in bone strength, which increases the risk of fracture" (Non-Patent Document 1; 2000 NIH consensus conference definition), Includes both primary and secondary osteoporosis.
- primary osteoporosis examples include regressive osteoporosis (postmenopausal osteoporosis and senile osteoporosis) and idiopathic osteoporosis (post-pregnancy osteoporosis, juvenile osteoporosis, etc.).
- Secondary osteoporosis is an osteoporosis that is induced by a cause of a specific disease or drug, such as a specific drug, rheumatoid arthritis, diabetes, hyperthyroidism, sexual dysfunction, immobility, nutrition, and other congenital diseases. Can be cited as the cause. Specific drugs include, for example, steroids. Diagnostic criteria for primary osteoporosis are well known (Non-Patent Document 10).
- osteoporosis having a high risk of fracture can be preferably mentioned.
- the osteoporosis having a high risk of fracture may be a patient having a risk factor such as low bone density, preexisting fracture, aging, and family history of femoral neck fracture. (Non-patent document 9).
- osteoporosis As described above, as a drug for treating osteoporosis, which has a high risk of bone fracture, a daily administration preparation or once-weekly preparation containing teriparatide or a salt thereof as an active ingredient was developed, and after approval for marketing, clinical It is actually used in the field. In addition, human anti-sclerostin antibody is being developed as a therapeutic drug for osteoporosis with a high risk of fracture. From these circumstances, those skilled in the art can easily and clearly recognize osteoporosis with a high risk of fracture.
- WRAX registered trademark of WHO (World Health Organization) is known as a tool for evaluating the absolute risk of fracture of an individual, and it is possible to calculate the probability (%) of an individual's fracture occurrence for the next 10 years. In daily medical care, it can be used as a screening tool for discriminating potentially high-risk fractured persons among asymptomatic elderly persons who are visiting a medical institution.
- the osteoporosis patient according to the present invention may be an osteoporosis patient having at least one or more of the above risk factors for fracture.
- an osteoporosis patient having three fracture risk factors of aging, preexisting bone fracture, and low bone density can be preferably exemplified.
- At least one of the risk factors for bone fracture satisfies a specific condition (eg, a specific threshold value or less, a specific threshold value or more, a specific numerical value range, presence or absence). It can also be an osteoporosis patient.
- a specific condition eg, a specific threshold value or less, a specific threshold value or more, a specific numerical value range, presence or absence. It can also be an osteoporosis patient.
- the osteoporosis patient according to the present invention is preferably an osteoporosis patient having a high risk of fracture.
- an osteoporosis patient satisfying the following three conditions can be preferably exemplified. 1) Over 65 years old. 2) One or more existing fractures. 3) Lumbar bone density is less than 80% of its young adult mean value (sometimes referred to as Young Adult Mean; YAM).
- the existing vertebral body fracture can be preferably mentioned as the existing fracture, and the number of existing fractures can be 1 or more and 5 or less. Further, the existing vertebral body fracture may be an existing vertebral body fracture that is mildly deformed (grade 1), moderately deformed (grade 2) or highly deformed (grade 3) (Non-Patent Document 9).
- Grade 1 are mild fractures in which vertebral body height is reduced by 20 to 25%
- Grade 2 are moderate fractures in which vertebral body height is reduced by 25 to 40%
- Grade 3 are: The severe fractures in which the vertebral body height is reduced by 40% or more can be mentioned.
- the osteoporosis patient according to the present invention can be an osteoporosis patient who does not satisfy at least one of the following 6 conditions. 1) Patients who are considered to have a high risk of developing osteosarcoma. 2) Patients with hypercalcemia. 3) Patients with primary malignant bone tumor or metastatic bone tumor. 4) Patients with metabolic bone diseases other than osteoporosis. 5) Patients with a history of hypersensitivity to the active ingredient of the therapeutic and / or prophylactic agent for osteoporosis of the present invention or other teriparatide preparations. 6) Pregnant women or women who may be pregnant.
- Patients considered to have a high risk of developing osteosarcoma include, for example, patients with Paget's disease of bone, patients with high levels of alkaline phosphatase, children, etc., and young patients whose epiphyses are not closed, and the effects on bone in the past. Mention may be made of patients who have received possible radiation treatments.
- the osteoporosis patient according to the present invention may be an osteoporosis patient who does not satisfy at least any one of the following 5 conditions. 1) Patients with hypotension. 2) Patients with renal disorders. 3) Patients with serious heart disease. 4) Patients with severe liver dysfunction. 5) Patients with urinary tract stones and those with a history.
- the osteoporosis patient according to the present invention can be an osteoporosis patient having mild or moderate renal impairment.
- Normal renal function, impairment, and extent of impairment can be distinguished based on creatinine clearance.
- creatinine clearance of 80 mL / min or more can be determined as normal renal function, 50 mL / min or more and less than 80 mL / min as mild renal dysfunction, and 30 mL / min or more but less than 50 mL / min as moderate renal dysfunction. ..
- the Cockcroft-Gault formula male: (140-age) ⁇ weight / (72 ⁇ serum creatinine value), female: 0.85 ⁇ (140-age) ⁇ weight / (72 X serum creatinine value) is mentioned as an example.
- the osteoporosis patient according to the present invention has at least any one of the following 18 factors that the patient has, and each of the factors has a specific condition (eg, a specific threshold or less, a specific threshold or more, a specific threshold or more).
- the patient may be an osteoporosis patient who satisfies the numerical range, type, presence or absence).
- Gender. 2) Age. 3) Height. 4) Weight. 5) BMI. 6) Years after menopause (limited to women who are menopausal). 7) Non-vertebral fracture injury history after 50 years old (limited to patients over 50 years old). 8) Non-vertebral body fracture injuries without significant external force after age 50 (limited to patients aged 50 and over). 9) Medical history affecting bone metabolism.
- the osteoporosis patient according to the present invention may be a male or female patient, a patient aged 65 or over and under 75 years old, a patient aged 75 or over and under 80 years old, a patient aged 80 or over, a lumbar bone density (YAM converted value) (%) is less than 60%, 60% or more and less than 70%, or 70% or more and less than 80%, the number of existing vertebral body fractures is zero, the number of existing vertebral body fractures is The number of patients is 1, the number of existing vertebral body fractures is 2-3, the number of existing vertebral body fractures is 4-5, the number of existing vertebral body fractures is 6 or more, etc. You can also
- the osteoporosis patient according to the present invention has at least one of the following 26 clinical examination items, and each item has a specific condition (eg, a specific threshold value or less, a specific threshold value or more, a specific numerical value range, etc.). ) Satisfied osteoporosis patient.
- General blood test items total 6 items (red blood cell count, hemoglobin, hematocrit, white blood cell count, white blood cell fraction, platelet count).
- Blood biochemical test items 14 items in total) (AST (GOT), ALT (GPT), alkaline phosphatase, total cholesterol, urea nitrogen, uric acid, creatinine, CPK, calcium, inorganic phosphorus, sodium, potassium, chlor, albumin ).
- Urinalysis items total 6 items (occult blood, protein, sugar, urobilinogen, bilirubin, pH).
- AST means aspartate aminotransferase (Glutamic acid oxaloacetic transaminase)
- ALT GPT
- GPT alanine aminotransferase (glutamate pyruvin).
- Acid transaminase Alanine aminotransferase (Glutamic pyruvic transaminase)
- CPK creatine phosphokinase.
- the osteoporosis patient according to the present invention has at least one of vital sign (sedentary systolic blood pressure, sitting diastolic blood pressure, pulse rate, etc.) items, and each item has a specific condition (eg: The patient may be an osteoporosis patient satisfying a specific threshold value or less, a specific threshold value or more, a specific numerical value range, etc.).
- vital sign sedentary systolic blood pressure, sitting diastolic blood pressure, pulse rate, etc.
- each item has a specific condition (eg: The patient may be an osteoporosis patient satisfying a specific threshold value or less, a specific threshold value or more, a specific numerical value range, etc.).
- the osteoporosis patient according to the present invention anti-drug antibody (eg, an antibody against teriparatide or a salt thereof, etc.) or a neutralizing antibody (eg: teriparatide or its) is accompanied by the administration of the therapeutic and / or prophylactic agent for osteoporosis of the present invention. It can also be an osteoporosis patient who can produce antibodies, such as those that reduce or eliminate salt activity.
- the osteoporosis patient according to the present invention has at least any one of the following 12 markers, each of which has a specific condition (eg, a specific threshold or less, a specific threshold or more, a specific numerical range).
- a specific condition eg, a specific threshold or less, a specific threshold or more, a specific numerical range.
- Etc. can also be a patient with osteoporosis.
- 1) Blood markers osteocalcin, P1NP, NTX, CTX, calcium, inorganic phosphorus, albumin, 25-hydroxyvitamin D fraction.
- Urinary markers NTX, calcium, inorganic phosphorus, creatinine).
- P1NP is a type I procollagen N-propeptide (Procollagen type I amino-terminal propeptide)
- NTX is a type I collagen cross-linked N-telopeptide (Crosslinked N-telopeptide of type I collagen).
- CTX means Type I collagen crosslinked C-telopeptide, respectively.
- examples of the osteoporosis patient according to the present invention include a patient having a blood osteocalcin concentration of less than 14.8 (ng / mL), a blood osteocalcin concentration of 14.8 (ng / mL) or more and 21.9 (ng). / ML), and a blood osteocalcin concentration of 21.9 (ng / mL) or more.
- the osteoporosis patients according to the present invention include, for example, patients having a blood P1NP concentration of less than 38.0 ( ⁇ g / L), blood P1NP concentration of 38.0 ( ⁇ g / L) or more and 58.5 ( ⁇ g). / L) or less than 58.5 ( ⁇ g / L).
- the osteoporosis patient for example, a patient having a blood P1NP concentration of less than 37.4 ( ⁇ g / L), a blood P1NP concentration of 37.4 ( ⁇ g / L) or more and 57.3 ( ⁇ g) / L) or less than 57.3 ( ⁇ g / L).
- the osteoporosis patient according to the present invention can also be a patient who has a history of treatment with a pretreatment drug for osteoporosis.
- a pretreatment drug for osteoporosis calcium drug, female hormone drug, SERM (selective estrogen receptor modulator), active vitamin D 3 drug, vitamin K 2 drug, calcitonin drug, parathyroid hormone drug, bisphosphonate drug, and denosumab can be mentioned.
- raloxifene and apeledoxifene can be preferably exemplified as SERMs, erdecalcitol, alfacalcidol and calcitriol as active vitamin D 3 drugs, and menatetrenone can be preferably exemplified as vitamin K 2 .
- examples of the bisphosphonate drug include etidronate, alendronate, risedronate, minodronate, and ibandronate.
- the calcitonin drug include salmon calcitonin and elcatonin.
- the parathyroid hormone drug include a preparation for daily administration and a preparation for once-weekly administration containing the above-mentioned teriparatide or a salt thereof as an active ingredient.
- the osteoporosis patient according to the present invention can also be an osteoporosis patient suffering from other diseases, that is, having a complication.
- Other diseases include diabetes, hypertension, dyslipidemia (hyperlipidemia, etc.), chronic kidney disease (CKD), rheumatoid arthritis, gout, hyperuricemia, dementia, cataract, presbycusis, dysuria, brain. Examples thereof include vascular disease and ischemic heart disease.
- the osteoporosis patient according to the present invention can be an osteoporosis patient in a state of requiring nursing care.
- the osteoporosis treatment and / or prevention agent of the present invention and the osteoporosis treatment method and / or prevention method of the present invention can be used in combination with other drugs.
- Other agents may be administered by the same or different routes, together or sequentially (ie at different times) with the osteoporosis treatment and / or prevention agent of the present invention.
- the other drug may be at least one of the above-mentioned pretreatment drugs for osteoporosis.
- the other drug may include a therapeutic and / or prophylactic drug for the above-mentioned complications.
- the other drug may be a basic drug (Ca, vD agent, etc.).
- Preferred basic drugs include vD 3 (vitamin D 3 ) agents, magnesium agents, and calcium agents. These may be used in any combination, and may be used as a compounding agent.
- a calcium agent containing vD 3 and magnesium can be preferably exemplified as a basic drug. Such combination is preferably taken once a day after dinner, and contains 400 IU of vD 3 and 30 mg of magnesium and 610 mg of calcium per dose.
- Non-Patent Document 15 When the therapeutic and / or prophylactic agent for osteoporosis of the present invention is subjected to a clinical test as a test drug, the evaluation can be carried out while the subject is taking the above-mentioned or a corresponding basic drug (Non-Patent Document 15).
- Non-patent Document 25 it is not clear that the fracture risk reduction of the combined use of vD and a calcium agent is unclear (Non-patent document 25), and the efficacy and safety when the basic drug is applied to both the test drug group and the control drug group. It is possible to consider the idea that the effect of the basic drug on the difference between the two groups will not be substantially observed. From these facts, when the therapeutic and / or prophylactic agent for osteoporosis of the present invention is used in clinical practice, it is not always necessary to use vD and a calcium agent.
- the therapeutic and / or prophylactic agent for osteoporosis of the present invention can take various dosage forms.
- the present agent is preferably an injection containing a pharmaceutically acceptable excipient and additive from the viewpoint of stability and the like.
- Excipients and additives are not particularly limited, but may include, for example, sugar alcohol (mannitol etc.), inorganic salt (sodium chloride etc.), sugar (sucrose etc.), amino acid (methionine etc.).
- the agent may or may not include a buffering agent.
- the pH of this agent can be adjusted appropriately and can be, for example, 3.5 to 5.5.
- the concentration of the active ingredient in this drug is not particularly limited, but may be, for example, 50 ⁇ g / mL or more, and may be 100 to 200 ⁇ g / mL.
- the active ingredients, excipients and additives are dissolved in an appropriate solvent (sterile water, buffer solution, physiological saline, etc.), and then filtered and / or sterilized with a filter or the like, Then, the present agent can be produced by filling and sealing the washed and sterilized container.
- an appropriate solvent sterile water, buffer solution, physiological saline, etc.
- examples of the filling container include an ampoule, a vial, a prefilled syringe, and a bag.
- the material of the container is not particularly limited, and examples thereof include glass and plastic. From the viewpoint of strength, ease of handling, safety and the like, plastic can be preferably exemplified as the material of the container.
- a pre-filled syringe with a needle that is pre-filled with a drug solution may be incorporated into an auto-injector as an automatic administration preparation. Since the therapeutic agent for osteoporosis, etc. according to the present invention shows sufficient safety, it can be used as a home-use self-administration preparation.
- the main purpose of the therapeutic and / or prophylactic agent for osteoporosis according to the present invention and the osteoporosis therapeutic method and / or preventive method of the present invention is to prevent or suppress bone fracture.
- the bone fracture according to the present invention includes both pathological bone fractures caused by osteoporosis, osteogenesis imperfections, bone tumors, etc., and traumatic bone fractures caused by traffic accidents, bruises, etc.
- a bone fracture caused by osteoporosis can be mentioned.
- the fracture according to the present invention includes both vertebral body fracture and non-vertebral body fracture.
- the non-vertebral body fracture is also not particularly limited, and examples thereof include fractures related to the proximal portion of the femur, the distal end of the radius, the proximal portion of the humerus, the tibia, the pelvis, and the ribs.
- a vertebral body fracture new vertebral body fracture, exacerbated vertebral body fracture, etc.
- a proximal femur fracture means a hip fracture of an elderly person and is understood as a fracture different from the fractures of the proximal femur (fractions of the proximal part of the femur).
- Patent document 9 examples of the fractures included in the femoral proximal fracture include, for example, a subchondral insufficiency fracture of the femoral head, a femoral neck fracture, a femoral neck fracture, a femoral neck fracture, and a femoral neck fracture.
- a trochanteric fracture of the femur and a subtrochanteric fracture of the femur Non-patent Document 9).
- proximal femoral fracture is sometimes referred to as the total proximal part of the femur from the viewpoint of emphasizing the whole.
- Vertebral body fractures are the most common osteoporotic fractures and are important as an index for diagnostic treatment of osteoporosis, and therefore their clinical significance is extremely high in prevention or inhibition (Non-Patent Document 9).
- the proximal femoral fracture causes deterioration of life function and QOL and is also related to the prognosis of the life (Non-Patent Document 9)
- the femoral proximal fracture is It is preferred that sufficient preventive and suppressive measures be taken.
- a vertebral body fracture can be judged as a morphological fracture by the degree of vertebral body deformation regardless of the presence or absence of clinical symptoms (Non-Patent Document 9). Morphological fractures can be classified into existing fractures and new fractures.
- a new fracture can be a fracture that is determined to have newly occurred by comparing X-ray images at two time points, and an existing fracture is determined by the degree of vertebral body deformation at one time point before the start of treatment. It can be a fractured bone.
- new bone fractures those that were not deformed before the start of treatment were deformed after the start of treatment are called new vertebral body fractures, and those with an increased degree of vertebral body deformation after the start of treatment are distinguished as worsening fractures. You can also do it.
- the new vertebral body fracture and the exacerbated vertebral body fracture are distinguished as described above.
- the vertebral body fracture according to the present invention includes both new vertebral body fracture and exacerbated vertebral body fracture.
- the degree of deformation can be classified into Grade according to the morphology of the whole vertebral body, and Grade 0 (normal), Grade 1 (vertebral body height is reduced by about 20 to 25% and vertebral body area is reduced by 10 to 20%).
- Grade2 vertebral body height approximately 25-40% reduction and vertebral body area 20-40% reduction
- Grade3 vertebral body height approximately 40% or more reduction and vertebral body area 40% or more reduction
- the classification of new and exacerbation can be performed according to the increase pattern of Grade according to the criteria of Genant.
- a fracture that is diagnosed with clinical symptoms such as pain can be referred to as a clinical fracture, and the clinical fracture can be classified into a clinical vertebral fracture and a clinical non-vertebral fracture.
- clinical non-vertebral fractures are simply referred to as non-vertebral fractures.
- the clinical symptom is, for example, acute pain in the back of the lower back, and can be confirmed by the subject's complaint.
- a fracture evaluation method using X-ray images and MRI is known per se, and for example, a quantitative evaluation method (QM method) and a semi-quantitative evaluation method (SQ method) are known.
- the SQ method is a method proposed by Genant et al. In 1993, and has been used in many clinical trials in Japan and overseas so far, and the evidence has been constructed, so that it can be more preferably used (Non-Patent Document 11).
- the method of Wu et al. And the method of Fukunaga et al. Can be used (Non-patent documents 11 to 13).
- the control drug which was confirmed to have fracture-inhibitory properties based on past clinical data, was subjected to the same test, and the fracture rate and test of the control drug obtained by conducting the test By comparing the incidence of drug fractures and comparing the incidence of untreated bone fractures with the subject drug in the same study, which can be inferred based on past clinical data, etc. It is also possible to evaluate the fracture-inhibiting effect of the test drug (fracture risk reduction, etc.) in the same test without using a placebo-controlled drug in the test.
- Bone strength is composed of two factors, bone density and bone quality. Generally, “bone density” can explain about 70% of bone strength, and the remaining 30% can be explained by “bone quality” ( Non-Patent Document 9). Not only the bone fracture suppressing effect but also the bone density increasing effect are known even in the daily administration preparation and the once-weekly administration preparation containing teriparatide or a salt thereof as an active ingredient (Non-Patent Documents 4, 5, 8, 9). ..
- the bone density typically refers to the amount of bone mineral in the lumbar spine.
- the lumbar vertebra is rich in cancellous bone, which has a high bone turnover rate, and thus is sensitive to changes in bone density detected by drug treatment.
- the bone mineral density can be indicated by the amount of bone mineral content of the radius, the second metacarpal bone, the femoral neck, and the calcaneus.
- the average value of young adults means the average value of bone density in 20-44 year olds.
- the bone density can be measured by a known method such as a dual energy X-ray absorption measurement method, a photodensitometry method, a photon absorption measurement method, a quantitative CT method, and a quantitative ultrasonic method.
- the degree of bone atrophy means the degree of bone loss on X-ray.
- the bone atrophy degree is classified into no bone atrophy degree, bone atrophy degree I degree, bone atrophy degree II degree, and bone atrophy degree III degree.
- No bone atrophy in the bone atrophy degree refers to a normal state, and specifically means a state in which the trabecular structure cannot be recognized because the trabecular bones in the vertical and horizontal directions are dense.
- Bone atrophy degree I means that the vertical trabeculae are conspicuous. Typically, the longitudinal trabeculae look thin but are still densely arranged, and the vertebral endplates are also conspicuous. means.
- the bone atrophy degree II degree in the bone atrophy degree means a state in which the longitudinal trabecular bone is coarse, the vertical trabecular bone looks thick, the arrangement is rough, and the vertebral body end plate is also pale.
- the bone atrophy degree III degree in the bone atrophy degree means a state in which the longitudinal trabecular bone is also unclear, the vertebral body shadow shows a blurred feeling as a whole, and the difference from the intervertebral disc shadow decreases.
- the degree of bone atrophy can be determined, for example, from a lumbar spine lateral X-ray image.
- the therapeutic and / or prophylactic agent for osteoporosis of the present invention from the viewpoint of efficacy, it is possible to observe changes in bone metabolism markers, increase in bone density, or suppression of bone fracture. Effectiveness is obtained by directly observing an increase in bone density or suppression of bone fracture in the administration mode in which the administration interval is 2 and 3 days apart (not including the administration day) within the week. Is preferably evaluated.
- Bone metabolism markers are roughly classified into bone formation markers and bone resorption markers.
- the bone formation marker may be a substance directly or indirectly produced from osteoblasts at each stage of osteoblast differentiation, and osteocalcin, P1NP and the like are known.
- the bone resorption marker can be a substance related to activation of osteoclasts and bone resorption, and NTX, CTX and the like are known.
- the difference between the bone formation marker and the bone resorption marker, which shows a rapid increase from the start of administration is called "Analytic window", and the mechanism of the increase in bone density from the early administration is particularly early.
- a change in bone metabolism marker for example, “Anabic window” is used as an index for treatment monitoring. You can also
- the administration mode of the twice-weekly administration method according to the present invention in which the administration interval within the week is every 2 and 3 days (not including the administration day), is related to the relationship between the bone metabolism marker and the efficacy. , Can be clearly distinguished from previous teriparatide therapy. Therefore, in the same administration mode, it is more preferable to directly observe the increase in bone density or the suppression of bone fracture, not the change in bone metabolism marker, when evaluating the efficacy.
- Non-patent Documents 14 to 15 studies in ovariectomized rats that are widely used as osteoporosis models have reported that the voids in cortical bone increase with the dose of teriparatide when the frequency of administration is high. (Non-patent document 14).
- teriparatide is used as a therapeutic drug for osteoporosis with a high risk of fracture, and it is reported that the target patients have an increase in voids in cortical bone due to aging and pathology. It has been reported that a therapeutic strategy that takes into account the patient's pathological condition and the characteristics of the pharmacological action of teriparatide is necessary to maximize the therapeutic effect of the drug (Non-Patent Document 14).
- NTX and CTX can be exemplified as a bone resorption marker closely related to voiding and porosity of cortical bone.
- the present invention in repeated administration, it may be an aspect in which there is an appropriate gap between administrations to such an extent that bone resorption is not continuously enhanced, and more specifically, for example,
- the treatment or prophylaxis in which the dose is 28.2 ⁇ g in terms of teriparatide can be exemplified, and among them, the twice-weekly administration method according to the present invention (however, one dose is 28.2 ⁇ g in terms of teriparatide) and An administration method in which the administration interval is 2 and 3 days apart (not including the administration day) can be preferably exemplified.
- Adverse events can be broadly classified into serious adverse events and non-serious adverse events, and the following six adverse events can be classified as serious adverse events. It can also be a serious adverse event. 1) Death (death). 2) Life-threatening (may cause death). 3) Those requiring hospitalization or extension of hospitalization period for treatment (hospitalization or extension of hospitalization period). 4) Those that fall into permanent or marked disability / dysfunction (disability). 5) What causes birth defects (birth defects). 6) Other medically important conditions (risk of disability, serious according to 1) to 4) above).
- adverse events can be broadly classified according to their severity as well as their seriousness and causality, and for example, the following three grades can be considered. 1) Mild: Transient and easily tolerated. 2) Moderate: To the extent that it interferes with normal activities. 3) Altitude: The degree to which normal activities are impossible.
- an adverse event is, for example, recovered / resolved, recovered / resolved, not recovered (not recovered / not resolved), or recovered but has an aftereffect (recovered) from the viewpoint of changes over time. / Resolved with sequence), dead, unknown.
- the method for safety comparison of one drug and another drug is not particularly limited, and, for example, focusing on a certain adverse event and comparing the frequency of occurrence, severity, causal relationship, outcome, and / or degree You can also do it.
- the two agents can be compared in terms of discontinuation of administration due to the whole adverse event or part thereof or the side effect whole or part thereof.
- Adverse events can include abnormal laboratory values and vital signs.
- the adverse event is not particularly limited, and may be classified according to a large organ classification (System Organ Class; SOC).
- System Organ Class System Organ Class; SOC
- the general classification of adverse events by organ can be exemplified as follows. 1) Infections and informations (infections and parasitic diseases) 2) Gastrointestinal disorders 3) Musculoskeletal and connective tissue disorders (musculoskeletal and connective tissue disorders) 4) Injury, positioning and procedure complications (disorders, poisoning, and procedural complications) 5) General disorders and administration site conditions (general / systemic disorder and condition of administration site) 6) Skin and subcutaneous tissue disorder (skin and subcutaneous tissue disorders) 7) Nervous system disorders 8) Respiratory, thoracic and medial disorders (respiratory, thoracic and mediastinal disorders) 9) Eye disorders 10) Metabolism and nutrition disorders 11) Investigations 12) Neoplasms benign, malignant and unspecified (incls cysts and polyps) (benign, malignant and unspecified neo
- ⁇ Examples of adverse events classified as “infectious diseases and parasitic diseases” include nasopharyngitis and influenza. Headache and dizziness are examples of adverse events classified as “neurological disorders”.
- Examples of adverse events classified as “gastrointestinal disorders” include nausea, vomiting, and constipation.
- Eczema can be exemplified as an adverse event classified into “skin and subcutaneous tissue disorders”.
- Osteoarthritis can be illustrated as an adverse event classified into “musculoskeletal and connective tissue disorders”. Fatigue, bleeding at injection site, and fever can be exemplified as adverse events classified into “general / systemic disorders and administration site condition”.
- a contusion can be exemplified as an adverse event classified into “disorders, poisoning, and treatment complications”.
- Non-Patent Document 9 As mentioned above, it has been reported that administration of teriparatide acetate often causes nausea, vomiting, headache, etc. (Non-Patent Document 9). Further, in clinical trials in which a preparation for daily administration containing teriparatide or a salt thereof as an active ingredient was provided, it was also reported that dizziness was significantly higher than that of the placebo group (Non-patent Document 9). It is also known that shock and transient loss of consciousness accompanied by a sudden and sudden drop in blood pressure may occur from immediately after the administration of the daily administration preparation or the once-weekly preparation containing the salt as an active ingredient to several hours after the administration. (Non-Patent Documents 4 and 8).
- the frequency of occurrence of at least one adverse event or side effect such as nausea, vomiting, headache, etc. (floating) dizziness, shock, hypotension, loss of consciousness
- a mode that suppresses the severity, severity, and / or degree as much as possible is preferable.
- Non-Patent Document 9 As described above, in general, it is reported that 52.1% of the medication status in the drug treatment of osteoporosis is dropped within 5 years after the start of the treatment, and further, the decrease in fracture suppression due to insufficient compliance with medication, Increasing need for facility utilization and stagnation of medical cost reduction are also regarded as problems (Non-Patent Document 9). As factors associated with poor compliance, the presence of pain, side effects, medication for gastrointestinal disorders, etc. are exemplified (Non-Patent Document 9).
- Test method Subjects were randomly assigned to either the study drug group or the control drug group, and as shown in FIG. 3, the study drug and the control drug placebo were assigned to each test drug group subject, and the test drug group was assigned to each test subject group as shown in FIG. On the other hand, the control drug and the test drug, placebo, were subcutaneously administered for 48 weeks by a double blind method (double dummy method). In addition, the subjects in each group took 2 tablets of the standard concomitant drug once a day after dinner.
- washout was performed when each subject had used an osteoporosis remedy within 8 weeks before obtaining consent from the clinical trial.
- the day after the last dose / injection of the pretreatment drug for the treatment of osteoporosis was set as the first day of washout, and the trial start date of the investigational drug should be 8 weeks after washout (56 days).
- the start of treatment with the investigational drug should not exceed 12 weeks (84 days) after obtaining consent.
- Investigators or investigators discontinue the clinical trial for a subject if they find that the subject meets the prescribed criteria after starting treatment with the study drug.
- Predetermined criteria are adverse events, lack of efficacy, no follow-up, judgment of investigator or investigator, significant deviation from protocol, non-compliance with study drug administration, subject's offer, or request. The person's judgment.
- test drug is an autoinjector formulation containing 0.2 g of the drug solution in one bottle, and when the whole amount is administered, 28.2 ⁇ g as teriparatide (30.3 ⁇ g as teriparatide acetate) is administered. , was a formulation.
- the drug solution is pre-filled in a prefilled syringe with a needle incorporated in the auto-injector, and the auto-injector is a device used for subcutaneous injection of the drug solution into the human body.
- test drug placebo is an autoinjector formulation that is indistinguishable in appearance comparison with the test drug, and is a formulation that does not substantially contain teriparatide.
- the control drug is a vial formulation, which is a lyophilized injectable formulation containing 63.3 ⁇ g as teriparatide (67.9 ⁇ g as teriparatide acetate) in one vial.
- the control drug is a formulation in which 56.5 ⁇ g of teriparatide is administered when a drug solution obtained by adding 1 mL of Japanese physiological saline solution and dissolving is administered by a syringe.
- Control drug placebo The placebo as a control drug is a lyophilized injectable formulation which is indistinguishable in appearance comparison with the control drug, and is a formulation substantially containing no teriparatide.
- Standard concomitant medications Standard concomitant drug, vitamin D 3 and magnesium compounding calcium agent (Shin Karushichuu (registered trademark) D 3; manufacturing vendor is Nitto Pharmaceutical Industries Ltd., distributor is Takeda) is.
- Two standard concomitant drugs include 1525 mg of precipitated calcium carbonate (610 mg as calcium), 118.4 mg of magnesium carbonate (30 mg as magnesium), 400 IU of cholecalciferol (vitamin D 3 ), and various additives.
- Frequency of twice a week The dosing interval at the frequency of twice a week was, in principle, 3 to 4 days (middle 2 days, middle 3 days).
- the basic dosing interval (3 to 4 day interval) here is the day of dosing of one of two consecutive administrations as the first day, and the other day on the fourth or fifth day. Means to administer. For example, when administered on one Monday of the week, the next administration day will be Thursday or Friday in principle as follows. (1 case of basic administration interval) Monday 1st day Administration Tuesday 2nd day Wednesday 3rd day Thursday 4th day or Friday 5th day Administration
- the test subject was an osteoporosis patient having all three fracture risk factors of “aging”, “existing fracture”, and “low bone density”. More specifically, the subject satisfies all of the following conditions (1) to (6) (satisfies the selection criteria) and does not satisfy any of the following conditions (7) to (25) (exclusion criteria: Satisfied), a patient with primary osteoporosis. Since the subject is an osteoporosis patient who has all three fracture risk factors of “aging”, “existing fracture”, and “low bone density” (the following conditions (2) to (4) are satisfied), Patients with high-risk osteoporosis.
- Selection criteria (1) Patients diagnosed with primary osteoporosis based on the diagnostic criteria for primary osteoporosis (2012 revised edition). (2) Men and women who are 65 years of age or older at the time of obtaining consent. (3) Patients with 1 to 5 existing fractures of vertebral bodies Th4 to L4 (4th thoracic vertebra to 4th lumbar vertebra). (4) Patients whose lumbar spine (L2-L4) bone density at the time of provisional registration is less than 80% of the average value of young adults. (5) Outpatients who can walk independently. (6) Patients who have acquired the self-injection procedure before the first administration of the study drug, and are judged by the investigator or the investigators to be able to manage and administer the study drug.
- Exclusion criteria (7) Patients diagnosed with secondary osteoporosis. (8) A patient having a disease exhibiting bone loss other than osteoporosis. (9) Patients with the following X-ray findings that are considered to affect the evaluation of lumbar spine bone density. -Severe vertebral body fracture is observed in any of the lumbar vertebrae L2 to L4. -A high degree of bone hardening is observed in any of the lumbar vertebrae L2 to L4. ⁇ Acknowledge high degree of scoliosis, lordosis and kyphosis. -Severe degenerative spondylotic changes are observed. -In addition, the bone evaluation committee determined that it was inappropriate, such as the inclusion of foreign matter. The "bone evaluation committee” is a member of the "bone evaluation committee” provided to uniformly evaluate bone mass evaluation and fracture evaluation of all patients. Each panel consists of experts in the diagnostic imaging of osteoporosis.
- “Serious liver disease” means that the AST (GOT) or ALT (GPT) value is 2.5 times or more the upper limit of the reference value or 100 IU / L or more in the test prescribed before provisional registration. "Severe heart disease” refers to Grade 2 shown in “Criteria for classification of severity of side effects of pharmaceuticals (June 29, 1992, Yakuho 80)" Means that it was determined to).
- Each patient assigned to the study drug group was subcutaneously injected with one study drug twice a week (self-injection into any part of the upper arm, thigh, or abdomen).
- the administration interval was 3 to 4 days (intermediate 2 days, intermediate 3 days).
- a solution obtained by dissolving 1 placebo of a control drug, placebo, in 1 mL of a physiological saline of Japanese Pharmacopoeia before use was subcutaneously injected once a week (outpatient injection).
- Each patient assigned to the control drug group received subcutaneous injection of one placebo drug (self-injection into any part of the upper arm, thigh, or abdomen) twice a week. Further, to the same patient, a solution obtained by dissolving 1 vial of a control drug in 1 mL of a Japanese physiological saline solution before use was subcutaneously injected once a week (outpatient injection).
- the primary evaluation item was the lumbar spine bone density change rate (second to fourth lumbar vertebrae).
- the secondary endpoints were the rate of change in femoral bone density, the rate of change in lumbar bone density (first to fourth lumbar vertebrae), the incidence of new vertebral body fractures, the incidence of exacerbated vertebral fractures, (new and exacerbated). Vertebral body fracture incidence, clinical fracture (clinical vertebral body fracture, non-vertebral body fracture) incidence, fragile clinical fracture incidence, fragile non-vertebral body fracture incidence, and bone metabolism markers.
- the safety evaluation items of the study were adverse events, vital signs, clinical tests, and immunogenicity.
- Bone density change rate measurement Table 1-1 below shows the method for measuring the rate of change in each of the lumbar spine bone density and the femur bone density.
- Evaluation of vertebral fractures The evaluation method of vertebral body fracture is shown in Table 1-2 below.
- the evaluation content includes the date of fracture occurrence (the day when the subject developed the clinical symptoms), the fracture site (vertebral body, proximal femur, radius, humerus, etc.), the presence or absence of large external force, and the basis for determining fracture (X Radiography / MRI, information from other departments / hospitals, etc.), X-ray / MRI date.
- Table 1-3 shows the inspection method of the bone metabolism marker.
- the survey items included adverse event names, date of onset, study drug administration status, disappearance date, outcome, severity classification, reason for seriousness, severity, causal relationship with study drug and standard concomitant drug, and adverse effects at the injection site. In the case of an event, it was the site and whether the trial was discontinued.
- Effectiveness analysis target The number of subjects who gave consent to treatment was 859, of which 553 registered for clinical trial and received treatment, 76 discontinued treatment, and 477 completed treatment.
- Table 2-1 below shows the background (outline) of 551 subjects who were subjected to efficacy analysis among the 553 treated patients. Table 2-1 shows that there is no significant background bias between the test drug group and the control drug group, and the fracture risk will be almost the same.
- Average dosing frequency and dosing period The average number of administrations and the average administration period in 553 treated patients are shown in Tables 2-2 and 2-3 below.
- the subject who received the test drug as the active drug (MN-10-T AI) received the placebo (MN-10-T Placebo) as the control drug, and the control drug as the active drug. Since the subject being administered as (MN-10-T) is receiving the placebo (MN-10-T AI Placebo) as the test drug (FIG. 29), the test drug active drug, the control drug placebo, and the test drug placebo were administered. The average number of administrations of the four control drugs and the active drug is calculated.
- Temporal changes in the mean bone mineral density change rates of the lumbar spine, femoral neck and proximal femur total Temporal changes in average rate of change in bone density of lumbar vertebrae (second to fourth lumbar vertebrae), lumbar vertebrae (first to fourth lumbar vertebrae), femoral neck and proximal femur total in subjects subject to efficacy analysis are shown in Tables 2-4 to 2-7 below. The numerical values in the table indicate the average rate of change (%) from the start.
- FIG. 4 shows the time-dependent change in the lumbar spine (second to fourth lumbar) bone mineral density change rate average value in the subjects of the efficacy analysis.
- the treatment with the study drug showed a higher rate of increase in all of the lumbar bone density, femoral neck bone density, and total femoral bone density in comparison with the control drug. Especially, the lumbar bone density was significantly higher.
- Efficacy analysis subjects are divided into subgroups using the lumbar spine (2nd to 4th lumbar vertebrae) bone density at the start or the number of existing vertebral body fractures as indices, and the lumbar vertebrae (2nd to 4th lumbar vertebrae)
- the results of analyzing the average value of the rate of change in bone density are shown in Tables 2-8 and 2-9 below.
- the numerical values in the table indicate the average rate of change (%) from the start.
- Non-Patent Document 9 It has been reported that the risk of vertebral body fracture increases 2.3 times when the lumbar vertebra bone density decreases by 1 SD (Non-Patent Document 9).
- the increase in lumbar vertebra density due to administration tends to increase with the decrease in lumbar vertebra density at the beginning
- the increase in the number of existing vertebral body fractures tended to decrease the increase in the lumbar spine bone density due to the administration.
- the treatment with the test drug is particularly excellent from the viewpoint of the effect of increasing the bone density of the femoral neck in patients with relatively low blood OC levels (eg, less than 15.2 (ng / mL)). It was
- Table 2-17 below shows the changes over time in the incidence of clinical vertebral body fractures by the Kaplan-Meier method among subjects analyzed for efficacy.
- treatment with the test drug is generally superior in terms of vertebral body fracture inhibition as compared with treatment with the control drug.
- Bone resorption markers Table 2-18 to 2-20 below shows the time course of bone resorption markers in the subjects analyzed for efficacy.
- the time course of bone resorption markers associated with treatment with the test drug was comparable or slightly suppressed compared to the time course of bone resorption markers associated with treatment with the control drug (Figs. 5-7).
- Non-patent document 17 reports that daily administration of the test drug enhances the bone resorption marker. Furthermore, in Non-Patent Document 27, since an erosion surface showing bone resorption is observed on the void surface of cortical bone produced by daily administration of the test drug (see Fig. 7 c, etc.), cortical bone porosity and bone It has been suggested that it is closely related to enhanced absorption. In light of the contents of these documents, the time course of the bone resorption marker in the twice weekly administration treatment is such that the twice weekly administration treatment increases the porosity of cortical bone more than the once weekly administration treatment. It is speculated that this suggests that the treatment does not show an increase in turnover.
- Bone formation markers The time course of bone formation markers in the efficacy analysis subjects is shown in Tables 2-21 and 2-22 below.
- the time course of osteogenic markers associated with treatment with the test drug was higher than that of osteogenic markers associated with treatment with the control drug (Figs. 8-9).
- the twice weekly administration treatment has a significantly higher rate of change in the bone formation marker as compared with the once weekly administration treatment. It was That is, it can be considered that the promotion of bone formation is excellent, and it can be considered that the twice-weekly administration treatment may show a greater rate of increase in bone density as compared with the once-weekly administration treatment.
- the subject of safety analysis was defined as a subject to whom the test drug or the control drug was administered at least once during the treatment period, and the following aggregate analysis was performed.
- the term “treatment-emergence event” (TEAE) means an adverse event that occurred during the treatment period.
- occurrence rate of adverse events and side effects in any disorder or condition such as nervous system disorder, gastrointestinal disorder, general / systemic disorder and administration site condition, heart disorder, vascular disorder was lower in the test drug group than in the control drug group.
- Non-Patent Documents 4 and 8 Non-Patent Documents 4 and 8).
- the average value of the change in systolic blood pressure showed a similar tendency at any test time point (0, 4, 12, 24, and 48 weeks).
- the average value showed a large decrease especially after 0, 4 and 12 weeks.
- the degree of decrease in blood pressure was -6.3 to -9.4 mmHg in the test drug group and -7.4 to -12.2 mmHg in the control drug group.
- the decrease in blood pressure in the test drug group was the blood pressure in the control drug group. Compared to the decline, it was moderate.
- the average diastolic blood pressure change (post-dose value-pre-dose value) showed the same declining trend at any test time (0, 4, 12, 24, and 48 weeks).
- the average value showed a large decrease after 0, 4 and 12 weeks.
- the degree of decrease in blood pressure was -4.2 to -6.3 mmHg in the test drug group and -4.3 to -8.0 mmHg in the control drug group.
- the decrease in blood pressure in the test drug group was the blood pressure in the control drug group. Compared with the decline, it was moderate.
- test drug group showed superior safety regardless of gender, but the incidence of side effects was markedly reduced in males in particular.
- ⁇ Continuity of treatment tended to be higher in the test drug group than in the control drug group.
- the rate of treatment discontinuation due to adverse events was lower in the study drug group than in the control drug group. Also, discontinuation due to adverse events within 24 weeks was 11 in the study drug group compared to 25 in the control drug group, and there were few discontinuations in the study drug group due to adverse events especially at the early stage of treatment. ..
- the treatment with the study drug group showed improvement in treatment continuity by reducing the incidence of adverse events such as nausea / vomiting or side effects, compared with the treatment with the control drug group.
- the week when the elapsed time from the day of administration of the placebo for the control drug to the day of administration of the placebo for the next control drug is within 6 days.
- the study drug has no administration interval, administration interval 1 day, administration interval 4 days , And the week when given at 5 day intervals.
- the following five tabulated analyzes were performed after defining the compliance rate of the 2-3 day administration interval.
- the efficacy evaluation items are the lumbar spine bone density change rate (second to fourth lumbar vertebrae), the femoral neck bone density change rate, the total femoral proximal part (femoral proximal total) bone density change rate, The incidence of clinical fracture and the incidence of non-vertebral body fracture were used.
- the safety evaluation items were the incidence of all side effects and the incidence of nausea (side effects).
- FIG. 25 shows the analysis result of the influence of the fluctuation of the specific value as a result.
- the average bone mineral density change rate (%) tended to increase as the 2-3 day administration interval compliance rate increased. Therefore, it was considered that the higher the ratio of the week in which the administration interval within the week (the administration day is not included) is the interval of 2 days and the interval of 3 days, the higher the therapeutic effect is obtained. More specifically, the same ratio shows a good therapeutic effect in the aspect of 70% or more, and a more remarkable therapeutic effect can be obtained in the aspect of 90% or more. Considering the positive correlation tendency, it was considered that the therapeutic effect would be maximized when the ratio was 100%.
- 2 to 3 day administration interval (3 or 4 day interval including the administration day) has a compliance rate of 0%, and is approximately 1 or 4 day interval (2 or 5 day interval including the administration day) per week.
- This result also suggests that it is useful to observe the dosing interval of 2-3 days (interval of 3,4 days including the dosing day) when administering twice a week. ing.
- Occurrence rate of clinical fractures and non-vertebral body fractures when differentiated by a specific value or more / less than each 3 day administration interval compliance rate The occurrence rate of clinical fractures and non-vertebral body fractures was calculated in the case of distinguishing by a specific value or more / less than every 2 to 3 day administration interval compliance rate. The results are shown in Tables 2-45 to 2-46 below.
- FIG. 26 shows the analysis results of the influence of the fluctuation of the specific value on the fracture occurrence rate (%) of the clinical fractures shown by the patients whose 2-3-day administration interval compliance rate is above the specific value (%). ..
- the fracture occurrence rate (%) tended to decrease as the compliance rate of the 2-3 day administration interval increased. Therefore, it was considered that the higher the ratio of the week in which the administration interval within the week (the administration day is not included) is the interval of 2 days and the interval of 3 days, the higher the therapeutic effect is obtained. More specifically, the same ratio shows a good therapeutic effect in the aspect of 70% or more, and a more remarkable therapeutic effect can be obtained in the aspect of 90% or more, and in addition, the same proportion and a strong therapeutic effect. Considering the positive correlation tendency, it was considered that the therapeutic effect would be maximized when the ratio was 100%.
- Osteocalcin (OC) in serum is widely used as a bone metabolism marker for observing the osteogenic action of daily preparations or once-weekly preparations containing teriparatide or a salt thereof as an active ingredient (non-patent document 5). Further, in the administration of the test drug according to the present invention, a peak of OC increase is observed approximately 4 weeks after the start of administration (FIG. 8). Therefore, FIG. 27 shows the analysis results of the influence of the fluctuation of the specific value on the OC indicated by the patient whose 2-3-day administration interval compliance rate is a certain specific value (%) or more at 4 weeks after the start of administration.
- Non-Patent Document 9 Parathyroid hormone drugs are known to be osteogenesis promoters (Non-Patent Document 9), and the discrepancy between bone formation markers and bone resorption markers is recognized as an efficacy index in daily treatment of osteoporosis using teriparatide. (Non-patent document 24). Therefore, the results of this analysis, which showed a tendency that there was a difference between the therapeutic effect and the bone formation marker OC in terms of the correlation with the 2-3-day administration interval adherence rate, are extremely remarkable in light of conventional teriparatide therapy findings. Was considered to be the target.
- FIG. 28 shows the analysis result of the influence of the fluctuation of the specific value on the nausea incidence rate (%) indicated by the patient whose 2-3-day administration interval compliance rate is equal to or higher than the specific value (%).
- the safer the treatment the higher the ratio of the week in which the dosing interval within a week (not including the dosing day) is the interval of 2 days and 3 days. More specifically, when the ratio is 70% or more, good safety is shown, and when the strong positive correlation tendency between the ratio and safety is also taken into consideration, the safety ratio is 100%. Was considered to be maximized.
- Test method In a 6-month-old female rabbit, the weekly dose of teriparatide was adjusted to 140 ⁇ g / kg, once a week, twice a week or seven times a week for 4 weeks, or a teriparatide-free control drug. Was subcutaneously administered 7 times a week for 4 weeks, and the effects on bone metabolism and bone tissue structure were examined (Table 2-54). In addition, the bone density and bone strength of the tibia were measured.
- the administered teriparatide solution was appropriately prepared by dissolving teriparatide acetate in water for injection, filtering, filling a vial, and dissolving the lyophilized preparation in a physiological saline solution at the time of use.
- Test results (1) Tibia bone density As a result of analysis of tibia bone density in divided areas, romiplostim significantly increased the bone density in the proximal part (1/5 site) where cancellous bone is high compared to the control group. At the site, bone density in the twice weekly group was higher than that in the once weekly group.
- the results of this test are for the lumbar vertebrae (second to fourth lumbar vertebrae), which have many cancellous bones as in the proximal tibia (60% are cancellous bones in the lumbar spine and 80% are cancellous bones in the vertebral body; The bone density of the twice weekly administration group was higher than that of the once weekly administration group, which is consistent with the test results of Example 1 (Table 2-4).
- Non-Patent Document 14 reports that high-frequency administration of teriparatide enhances bone turnover and that the increase in porosity of cortical bone due to teriparatide is strongly influenced by the administration frequency. In this Example, the twice weekly administration treatment did not show an increase in bone turnover that would increase the cortical bone porosity, regardless of the doubling of the administration frequency.
- Non-Patent Document 17 reports that daily administration of a test drug enhances a bone resorption marker. Furthermore, in Non-Patent Document 27, an erosive surface showing bone resorption is observed on the void surface of cortical bone produced by daily administration of the test drug (see Fig. 7c, etc.), and therefore cortical bone porosity and bone It has been suggested that it is closely related to enhanced absorption. In Example 1, the time course of the bone resorption marker associated with the twice weekly administration treatment was equal to or slightly suppressed as compared with the time course of the bone resorption marker associated with the once weekly administration treatment (FIGS. 5 to 7).
- Example 1 was supported by the results of the rabbit test of Example 2.
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Abstract
Description
[1]1回当たり28.2μgのテリパラチド又はその塩が週2回の頻度で投与されることを特徴とする、テリパラチド又はその塩を有効成分として含有する骨粗鬆症治療及び/又は予防剤。
[2]週内の2回の投与間隔(投与日は含まれない)が2日及び3日間隔である、前記[1]に記載の骨粗鬆症治療及び/又は予防剤。
[3]週2回の頻度で投与された期間の週数をnとし、そのn週のうち週内の2回の投与の間隔が2日及び3日である(投与日は含まれない)週の数をmとした場合、(m/n)×100(%)が70%又はそれ以上である、前記[1]に記載の骨粗鬆症治療及び/又は予防剤。
[4]皮下に投与される、前記[1]~[3]のいずれかに記載の骨粗鬆症治療及び/又は予防剤。
[5]腰椎骨密度がその若年成人平均値の60%未満である者に投与される、前記[1]~[4]のいずれかに記載の骨粗鬆症治療及び/又は予防剤。
[6]既存椎体骨折が1個である者に投与される、前記[1]~[4]のいずれかに記載の骨粗鬆症治療及び/又は予防剤。
[7]血清オステオカルシン濃度が15.2(ng/mL)未満である者に投与される、前記[1]~[4]のいずれかに記載の骨粗鬆症治療及び/又は予防剤。
[8]年齢が80歳以上の者に投与される、前記[1]~[4]のいずれかに記載の骨粗鬆症治療及び/又は予防剤。
[9]男性に投与される、前記[1]~[4]のいずれかに記載の骨粗鬆症治療及び/又は予防剤。
[10]骨折の危険性の高い骨粗鬆症患者に投与される、前記[1]~[4]のいずれかに記載の骨粗鬆症治療及び/又は予防剤。
[11]加齢、既存骨折、低骨密度の全ての骨折危険因子を有する骨粗鬆症患者に投与される、前記[1]~[4]のいずれかに記載の骨粗鬆症治療及び/又は予防剤。
[12]以下の(1)~(3)の条件を充足する骨粗鬆症患者へ投与される、前記[1]~[4]のいずれかに記載の骨粗鬆症治療及び/又は予防剤:
(1)年齢が65歳以上であること;
(2)既存椎体骨折が1個以上5個以下であること;
(3)腰椎骨密度がその若年成人平均値の80%未満であること。
本発明において、ヒトPTH(1-34)は、ヒト副甲状腺ホルモンであるヒトPTH(1-84)のアミノ酸配列において、N末端側からみて第1番目から第34番目までのアミノ酸残基からなる部分アミノ酸配列で示されるペプチドである。
本発明の骨粗鬆症治療及び/又は予防剤に含有される、ならびに、本発明の骨粗鬆症治療方法及び/又は予防方法で使用される、有効成分の1回当たりの投与量は特に限定されないが、好適には以下を例示できる。
本発明の骨粗鬆症治療及び/又は予防剤ならびに本発明の骨粗鬆症治療方法及び/又は予防方法は、週2回の頻度で投与されることを特徴の1つとする。
本発明の骨粗鬆症治療及び/又は予防剤ならびに本発明の骨粗鬆症治療方法及び/又は予防方法の投与経路は特に限定されず、静脈、皮下、又は、筋肉内に投与され得る。中でも、皮下投与を好ましく例示することができる。
本発明の骨粗鬆症治療及び/又は予防剤ならびに本発明の骨粗鬆症治療方法及び/又は予防方法の投与期間は特に限定されず、患者に応じた担当医師の処方等により適宜決定され得る。
(6-1)疾患:
本発明の骨粗鬆症治療及び/又は予防剤ならびに本発明の骨粗鬆症治療方法及び/又は予防方法は、骨粗鬆症の治療及び/又は予防の目的をもって投与されることを特徴の1つとする。
本発明に係る骨粗鬆症患者は、前記の骨折の危険因子を少なくとも1以上有する骨粗鬆症患者であることができる。このような患者として、加齢、既存骨折、及び、低骨密度の3つの骨折危険因子を有する骨粗鬆症患者を好ましく例示できる。
1)65歳以上である。
2)既存骨折が1個以上ある。
3)腰椎骨密度がその若年成人平均値(Young Adult Mean;YAMと称することもある)の80%未満である。
1)骨肉腫発生危険性が高いと考えられる患者。
2)高カルシウム血症の患者。
3)原発性の悪性骨腫瘍もしくは転移性骨腫瘍のある患者。
4)骨粗鬆症以外の代謝性骨疾患の患者。
5)本発明の骨粗鬆症治療及び/又は予防剤の有効成分又は他のテリパラチド製剤に対し過敏症の既往歴のある患者。
6)妊婦又は妊娠している可能性のある婦人。
1)低血圧の患者。
2)腎障害のある患者。
3)重篤な心疾患のある患者。
4)重篤な肝機能障害を有する患者。
5)尿路結石のある患者及びその既往歴のある患者。
1)性別。
2)年齢。
3)身長。
4)体重。
5)BMI。
6)閉経後年数(女性であり、閉経している患者に限る)。
7)50歳以降の非椎体骨折受傷歴(50歳以上の患者に限る)。
8)50歳以降の大きな外力を伴わない非椎体骨折受傷歴(50歳以上の患者に限る)。
9)骨代謝に影響を及ぼす既往歴。
10)喫煙。
11)アルコール摂取。
12)両親の大腿骨骨折歴。
13)骨粗鬆症の前治療薬。
14)25-ヒドロキシビタミンD。
15)既存椎体骨折数。
16)腰椎骨密度(YAM換算値)(%)。
17)大腿骨頸部骨密度(YAM換算値)(%)。
18)大腿骨近位部Total骨密度(YAM換算値)(%)。
1)血液一般検査項目(計6項目)(赤血球数、ヘモグロビン、ヘマトクリット、白血球数、白血球分画、血小板数)。
2)血液生化学検査項目(計14項目)(AST(GOT)、ALT(GPT)、アルカリフォスファターゼ、総コレステロール、尿素窒素、尿酸、クレアチニン、CPK、カルシウム、無機リン、ナトリウム、カリウム、クロール、アルブミン)。
3)尿検査項目(計6項目)(潜血、蛋白、糖、ウロビリノーゲン、ビリルビン、pH)。
1)血中マーカー(オステオカルシン、P1NP、NTX、CTX、カルシウム、無機リン、アルブミン、25-ヒドロキシビタミンD分画)。
2)尿中マーカー(NTX、カルシウム、無機リン、クレアチニン)。
本発明の骨粗鬆症治療及び/又は予防剤ならびに本発明の骨粗鬆症治療方法及び/又は予防方法は、他の薬剤と併用することもできる。他の薬剤は、本発明の骨粗鬆症治療及び/又は予防剤と一緒に又は逐次に(すなわち別々の時間に)、同一又は異なる経路で投与され得る。
本発明の骨粗鬆症治療及び/又は予防剤は、種々の製剤形態をとり得る。一般的には、本剤は、安定性等の観点から薬学的に許容される賦形剤及び添加物を含有する注射剤とすることが好ましい。
本発明に係る骨粗鬆症の治療及び/又は予防剤ならびに本発明の骨粗鬆症治療方法及び/又は予防方法の主目的は、骨折を予防又は抑制することである。
本発明に係る骨折は、骨粗鬆症・骨形成不全・骨腫瘍などを原因とする病的骨折、交通事故・打撲などを原因とする外傷性骨折のいずれをも含む。好ましくは、骨粗鬆症を原因とする骨折を挙げることができる。
骨強度は、骨密度と骨質の2つの要因からなり、一般的に、「骨密度」は骨強度のおよそ70%を説明し、残りの30%程度は「骨質」により説明することができる(非特許文献9)。テリパラチド又はその塩を有効成分とする連日投与用製剤や週1回投与用製剤においても、骨折抑制効果のみならず骨密度増加効果も知られている(非特許文献4、5、8、9)。
ある時点aにおける骨密度変化率(%)={(当該時点の骨密度-投与開始時の骨密度)/投与開始時の骨密度}×100
骨代謝マーカーの変動は、骨折の予防又は抑制及び骨密度の増加と関係している。したがって、骨粗鬆症治療剤を、有効性の面から評価等する際、被験者由来の生体試料(血液試料、尿試料など)における骨代謝マーカー値を測定し、その変動(例:投与前の値と投与後の値の差など)を確認することも有用であると考えられている(非特許文献9)。
(10-1)有害事象及び副作用:
薬剤を投与された者に生じた全ての好ましくないまたは意図しない疾病やその徴候を有害事象(Adverse event;AE)と称することができる。
1)死に至るもの(死亡)。
2)生命を脅かすもの(死亡のおそれ)。
3)治療のため入院または入院期間の延長が必要となるもの(入院または入院期間の延長)。
4)永続的または顕著な障害・機能不全に陥るもの(障害)。
5)先天異常を来すもの(先天異常)。
6)その他の医学的な重要な状態(障害のおそれ、上記1)~4)に準じて重篤)。
1)軽度: 一過性で容易に耐えられる程度。
2)中等度:通常の活動に支障を来す程度。
3)高度: 通常の活動を不可能にする程度。
1)Infections and infestations(感染症及び寄生虫症)
2)Gastrointestinal disorders(胃腸障害)
3)Musculoskeletal and connective tissue disorders(筋骨格系及び結合組織障害)
4)Injury, poisioning and procedural complications(障害、中毒、及び処置合併症)
5)General disorders and administration
site conditions(一般・全身障害及び投与部位の状態)
6)Skin and subcutaneous tissue disorders(皮膚及び皮下組織障害)
7)Nervous system disorders(神経系障害)
8)Respiratory,thoracic and mediastinal disorders(呼吸器、胸郭及び縦隔障害)
9)Eye disorders(眼障害)
10)Metabolism and nutrition disorders(代謝及び栄養障害)
11)Investigations(臨床検査)
12)Neoplasms benign,malignant and unspecified(incl cysts and polyps)(良性、悪性及び詳細不明の新生物(嚢胞及びポリープを含む))
13) Ear and labyrinth disorders(耳及び迷路障害)
14)Cardiac disorders(心臓障害)
15)Vascular disorders(血管障害)
前述の通り、一般的に、骨粗鬆症の薬物治療における服薬状況は、治療開始後5年以内に52.1%が脱落してしまうことが報告され、さらに、服薬遵守不足による、骨折抑制の低下、施設利用の必要性の高まり、医療費削減の停滞も問題視されている(非特許文献9)。服薬遵守不良に関連する要因として、痛みの存在、副作用、胃腸障害に対する服薬などが例示されている(非特許文献9)。また、一方、テリパラチド又はその塩を有効成分とする製剤は、治療継続率の低さも指摘されており、12ヶ月間にわたる治療継続率は34.9%であることが報告されている(非特許文献22)。
被験者を被験薬群と対照薬群のいずれかに無作為に割り付け、図3に示すように、被験薬群の各被験者に対しては被験薬及び対照薬プラセボを、対照薬群の各被験者に対しては対照薬及び被験薬プラセボを、二重盲検法(ダブルダミー法)にて、48週間にわたって皮下投与した。また、いずれの群の被験者も標準併用薬2錠を1日1回の頻度で夕食後に服薬した。
被験薬は、1本中に0.2gの薬液を含有するオートインジェクター製剤であって、1本全量を投与した際には、テリパラチドとして28.2μg(テリパラチド酢酸塩として30.3μg)投与される、製剤であった。薬液は、オートインジェクターに組み込まれた針付プレフィルドシリンジに予め充填されており、オートインジェクターは、人体への薬液の皮下注射に用いる器具である。
被験薬プラセボは、被験薬との外観比較において識別不能なオートインジェクター製剤であって、テリパラチドを実質的に含有しない製剤である。
対照薬は、バイアル製剤であって、1バイアル中にテリパラチドとして63.3μgを含有する(テリパラチド酢酸塩として67.9μg)凍結乾燥注射用製剤である。なお、対照薬は、日局生理食塩液1mLを加えて溶解して得た薬液をシリンジで投与する場合、テリパラチドとして56.5μg投与される、製剤である。
対照薬プラセボは、対照薬との外観比較において、識別不能な凍結乾燥注射用製剤であって、テリパラチドを実質的に含有しない製剤である。
標準併用薬は、ビタミンD3及びマグネシウム配合のカルシウム剤(新カルシチュウ(登録商標)D3;製造販売元は日東薬品工業株式会社であり、販売元は武田薬品工業株式会社である)である。標準併用薬2錠中には、沈降炭酸カルシウム1525mg(カルシウムとして610mg)、炭酸マグネシウム118.4mg(マグネシウムとして30mg)、コレカルシフェロール(ビタミンD3)400IU、及び各種添加物が含まれる。
週2回の頻度における投与間隔は、原則的に、3~4日間隔(中2日、中3日間隔)とした。ここでの原則的な投与間隔(3~4日間隔)は、連続する2回の投与のうちいずれか一方の投与の投与日を1日目として、4日目又は5日目にもう一方の投与をすることを意味する。例えば、ある週の月曜日に投与した場合、次の投与日は、以下のように、原則的に、木曜日又は金曜日となる。
(原則的な投与間隔の1例)
月曜日 1日目 投与
火曜日 2日目
水曜日 3日目
木曜日 4日目、又は、金曜日 5日目 投与
被験者は、「加齢」、「既存骨折」、「低骨密度」の3つの骨折危険因子全てを有する骨粗鬆症患者であった。より具体的には、被験者は、以下の条件(1)~(6)を全て満たし(選択基準を満たし)、以下の(7)~(25)の条件のいずれをも満たさない(除外基準を満たす)、原発性骨粗鬆症患者であった。被験者は、「加齢」、「既存骨折」、「低骨密度」の3つの骨折危険因子全てを有する(以下の条件(2)~(4)を満たす)骨粗鬆症患者であることから、骨折の危険性の高い骨粗鬆症患者である。
(1)原発性骨粗鬆症の診断基準(2012年度改訂版)に基づき原発性骨粗鬆症と診断された患者。
(2)同意取得時の年齢が65歳以上の男女。
(3)椎体のTh4~L4(第4胸椎~第4腰椎)の既存骨折が1個以上5個以内の患者。
(4)仮登録時の腰椎(L2~L4)骨密度が若年成人平均値の80%未満の患者。
(5)自立歩行可能な外来患者。
(6)被験薬等の初回投与前に、自己注射手技を習得し、被験薬等の管理及び投与が可能であると治験責任医師又は治験分担医師が判断した患者。
(7)続発性骨粗鬆症と診断された患者。
(8)骨粗鬆症以外の骨量減少を呈する疾患を有する患者。
(9)腰椎骨密度の評価に影響を及ぼすと考えられる以下のX線所見を有する患者。
・腰椎L2~L4のいずれかに高度の椎体骨折を認める。
・腰椎L2~L4のいずれかに高度の骨硬化を認める。
・高度の側弯、前弯、後弯を認める。
・高度の変形性脊椎症性変化を認める。
・その他、異物の混入など、骨評価委員が不適当と判定した。
なお、「骨評価委員」とは、全患者の骨量評価及び骨折評価を均一に評価するために設けられた「骨評価委員会」を構成する委員である。各々の評価委員は、骨粗鬆症の画像診断のエキスパートで構成されている。
(11)椎体骨折を疑うような急性疼痛を訴えている患者{同意取得12週間(84日)前から治療開始日までに急性の腰背部痛が発現または増強し、安静及び消炎鎮痛剤などの加療が必要な患者}。
(12)問診の信頼性が低いと判断された患者(少なくとも認知症の患者は除外)。
(13)重篤な腎疾患、肝疾患または心疾患を有する患者(ただし、ここで「重篤な腎疾患」とは、仮登録前に規定された検査で血清クレアチニン値が2mg/dL以上を示すことを意味し、「重篤な肝疾患」とは、仮登録前に規定された検査でAST(GOT)またはALT(GPT)値が基準値上限の2.5倍以上または100IU/L以上を示すことを意味し、「重篤な心疾患」とは、「医薬品の副作用の重篤度分類基準について(平成4年6月29日薬安発第80号)」に示すグレード2を参考に判断されたことを意味する)。
(15)仮登録前に規定された検査で血清カルシウム値が11.0mg/dL以上の患者。
(16)仮登録前に規定された検査でアルカリフォスファターゼ値が基準値上限の2倍以上の患者。
(17)骨ページェット病の患者。
(18)原発性の悪性骨腫瘍もしくは転移性骨腫瘍の合併、または既往がある患者。
(19)悪性骨腫瘍の合併または過去5年以内に既往のある患者。
(20)過去に骨への影響が考えられる放射線治療を受けた患者。
(21)過去にテリパラチド製剤または抗RANKL抗体製剤の投与を受けた患者。
(22)同意取得前52週(364日)以内にビスホスホネート製剤の投与を受けた患者(ただし、薬剤の用法で一定間隔の期間が設定されている薬剤では、同意取得前52週(364日)にその期間を加えた日数とする)。
(23)他の治験薬を同意取得前26週(182日)以内に投与された患者。
(A)カルシトニン製剤。
(B)活性型ビタミンD3製剤。
(C)ビタミンK製剤。
(D)イプリフラボン製剤。
(E)エストロゲン製剤。
(F)SERM製剤。
(G)蛋白同化ホルモン製剤。
(25)その他、治験責任医師または治験分担医師が本治験の実施にあたり不適当と判断した患者。
被験者を被験薬群または対照薬群のいずれかに無作為に割り付け、図3に示すように、被験薬群の各被験者に対しては被験薬及び対照薬プラセボを、対照薬群の各被験者に対しては対照薬及び被験薬プラセボを、二重盲検法(ダブルダミー法)にて、48週間にわたって皮下投与した。また、いずれの群の被験者も標準併用薬2錠を1日1回の頻度で夕食後に服薬した。
腰椎骨密度及び大腿骨骨密度の各骨密度変化率の測定方法を下記表1-1に示す。
椎体骨折の評価方法を下記表1-2に示す。
治療開始から48週後(中止時)までに、被験者の訴え(臨床症状)があり、かつ治験責任医師または治験分担医師がX線写真またはMRIなどにより骨折を確認した場合は臨床骨折とした。特に、被験者が腰背部の急性疼痛を訴える場合は、X線撮影を行い骨折の有無を確認した。
骨代謝マーカーの検査方法を下記表1-3に示す。
治験責任医師または治験分担医師は、各被験者の同意取得日~最終投与日から1週間後にわたって、被験者からの自発的報告、問診、及び各種検査により、有害事象を調査した。
治験責任医師または治験分担医師は、検体(血液)を各検査日の治験薬投与前に採取し、保存した。検体回収後に治験薬に対する抗薬物抗体を測定した。抗薬物抗体が陽性であった検体のみ中和抗体を測定した。
2.1.有効性の解析対象者:
治療同意を示した被験者は859名であり、その内553名が治験登録し、治療を受け、76名が治療を中断し、477名が治療を完結した。治療を受けた553名のうち、有効性の解析対象者である551名の背景(概要)を以下の表2-1に示す。表2-1は、被験薬群と対照薬群の間で、背景に大きな偏りはなく、骨折リスクもほぼ同等であろうことを示している。
治療を受けた553名における、平均投与回数及び平均投与期間を以下の表2-2及び2-3に示す。なお、平均投与回数について、被験薬を実薬(MN-10-T AI)として投与している被験者は対照薬のプラセボ(MN-10-T Placebo)を投与しており、対照薬を実薬(MN-10-T)として投与している被験者は被験薬のプラセボ(MN-10-T AI Placebo)を投与しているため(図29)、被験薬実薬、対照薬プラセボ、被験薬プラセボ、対照薬実薬の4剤の平均投与回数を算出している。
有効性の解析対象者における、腰椎(第2~第4腰椎)、腰椎(第1~第4腰椎)、大腿骨頚部及び大腿骨近位部totalそれぞれの骨密度変化率平均値の時間的推移を以下の表2-4~2-7に示す。表内の数値は、開始時からの変化率平均値(%)を示す。
有効性の解析対象者における、カプラン・マイヤー法による新規椎体骨折発生率及び増悪椎体骨折発生率の時間的推移等を以下の表2-15及び2-16に示す。
有効性の解析対象者における、カプラン・マイヤー法による臨床椎体骨折発生率の時間的推移等を以下の表2-17に示す。
有効性の解析対象者における、骨吸収マーカーの時間的推移を以下の表2-18~2-20に示す。
有効性の解析対象者における、骨形成マーカーの時間的推移を以下の表2-21及び2-22に示す。
安全性の解析対象は、治療期において被験薬又は対照薬を少なくとも1回以上投与された被験者と定義し、以下の集計解析を行った。Trearment-emergent adverse event(TEAE)とは、治療期において発現した有害事象を意味する。
2.9.1.解析方法:
被験薬群のうち48週間にわたる治療を完遂した被験者242名(以降、治療完遂被験薬群)を対象とし、各被験者について、投与全期間週数である48週のうち、週内の投与間隔(投与日は含まれない)が2日及び3日間隔である週が占める割合(%)(以降、2~3日投与間隔遵守割合)を算出した。その際、以下の条件(1)又は(2)を充足する週については、週内の投与間隔(投与日は含まれない)が2日及び3日間隔である週に該当しないものとした。
(1)対照薬プラセボを投与された日から次の対照薬プラセボを投与された日までの経過期間が6日以内である場合のその週。
(1)2~3日投与間隔遵守割合が70%以上である治療完遂被験薬群と2~3日投与間隔遵守割合が70%未満である治療完遂被験薬群の有効性及び安全性の対比解析。
(2)2~3日投与間隔遵守割合が75%以上である治療完遂被験薬群と2~3日投与間隔遵守割合が75%未満である治療完遂被験薬群の有効性及び安全性の対比解析。
(3)2~3日投与間隔遵守割合が80%以上である治療完遂被験薬群と2~3日投与間隔遵守割合が80%未満である治療完遂被験薬群の有効性及び安全性の対比解析。
(4)2~3日投与間隔遵守割合が85%以上である治療完遂被験薬群と2~3日投与間隔遵守割合が85%未満である治療完遂被験薬群の有効性及び安全性の対比解析。
(5)2~3日投与間隔遵守割合が90%以上である治療完遂被験薬群と2~3日投与間隔遵守割合が90%未満である治療完遂被験薬群の有効性及び安全性の対比解析。
2.9.2.1.平均投与回数及び平均投与期間:
治療完遂被験薬群の242名を対象に、投与間隔遵守割合毎に平均投与回数及び平均投与期間を算出した。その結果を以下の表2-40に示す。
各2~3日投与間隔遵守割合を特定値以上/未満で区別した場合における腰椎、大腿骨頸部及び大腿骨近位部totalそれぞれの骨密度変化率平均値(%)を算出した。その結果を以下の表2-41~2-43に示す。
2~3日投与間隔遵守割合毎に特定値以上/未満で区別した場合における臨床骨折及び非椎体骨折の発生割合を算出した。その結果を以下の表2-45~2-46に示す。
投与間隔遵守割合毎に特定値以上/未満で区別した場合における骨代謝マーカー(尿中NTX(u-NTX)、血清NTX(s-NTX)、CTX、OC、P1NP)の経時的推移を算出した。その結果を以下の表2-47~表2-51に示す。
6ヵ月齢の雌性のウサギに、テリパラチドの週当たり用量を140μg/kg に揃えて、週1 回、週2 回もしくは週7回の頻度で4週間にわたって、あるいは、テリパラチドを含まない対照薬を週7回の頻度で4週間にわたって皮下投与し、骨代謝および骨組織構造に与える影響を検討した(表2-54)。併せて、脛骨の骨密度および骨強度を測定した。投与されたテリパラチド溶液は、テリパラチド酢酸塩を注射用水で溶解、ろ過後、バイアルに充填し、凍結乾燥した製剤を用時に生理食塩液に溶解させることで適宜に調製した。
(1)脛骨骨密度
脛骨骨密度を分割領域で解析した結果、本薬は海綿骨の多い近位部(1/5 部位)の骨密度を対照群と比べて顕著に増加させ、本部位において週2 回投与群の骨密度は週1 回投与群よりも高値であった。本試験結果は、脛骨近位部と同様に海綿骨の多い腰椎(第2~4腰椎)(腰椎では60%が海綿骨であり、椎体では80%が海綿骨;非特許文献26)において、週2回投与群の骨密度は週1回投与群よりも高値であったことを示した実施例1試験結果(表2-4)と符合する。
週7 回投与群では、皮質骨内膜面の海綿骨化、皮質骨内部の多数の空隙(多孔化)、ならびに層板構造の乱れが観察されたが、週1 回および週2 回投与群ではいずれの所見も観察されなかった。
非特許文献14は、テリパラチド高頻度投与が骨代謝回転を亢進することやテリパラチドによる皮質骨空隙率増加は投与頻度の影響を強く受けることが示唆されることを報告している。本実施例において、週1回投与治療に対して、週2回投与治療はその投与頻度の倍化に関わらず、皮質骨空隙率を増加せしめるような骨代謝回転の亢進が認められなかったことは、非特許文献14に照らすと意外で画期的な結果と考えられた。
また、非特許文献17は、被験薬の連日投与が、骨吸収マーカーを亢進させること等を報告している。さらに、非特許文献27において、被験薬の連日投与により生じた皮質骨の空隙表面には骨吸収を示す浸食面が認められることから(Fig.7 cなど参照)、皮質骨の多孔化と骨吸収の亢進と深い関係があることが示唆されている。
実施例1において、週2回投与治療に伴う骨吸収マーカーの時間推移は、週1回投与治療に伴う骨吸収マーカーの時間推移と比較して同等又はやや抑制されていた(図5~7)が、このような機序を通じて、週2回投与治療は、週1回投与治療に対して、投与頻度の倍化に関わらず皮質骨空隙率を増加せしめるような骨代謝回転の亢進を示さない治療であろうことを推察できる。従って、実施例1での効果は、実施例2のウサギでの試験の結果によって支持されるものであった。
Claims (4)
- 1回当たり28.2μgのテリパラチド又はその塩が週2回の頻度で投与されることを特徴とする、テリパラチド又はその塩を有効成分として含有する骨粗鬆症治療及び/又は予防剤。
- 週内の2回の投与間隔(投与日は含まれない)が2日及び3日間隔である、請求項1に記載の骨粗鬆症治療及び/又は予防剤。
- 週2回の頻度で投与された期間の週数をnとし、そのn週のうち週内の2回の投与の間隔が2日及び3日である(投与日は含まれない)週の数をmとした場合、(m/n)×100(%)が70%又はそれ以上である、請求項1に記載の骨粗鬆症治療及び/又は予防剤。
- 皮下に投与される、請求項1~3のいずれか1項に記載の骨粗鬆症治療及び/又は予防剤。
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CA3101326A CA3101326C (en) | 2018-10-29 | 2019-07-31 | Method for preventing or treating osteoporosis, characterized by administering teriparatide or salt thereof at a frequency of twice a week |
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