Patent Description:
Osteoporosis is defined as "a skeletal disease characterized by compromised bone strength predisposing a person to an increased risk of fracture" (Non-Patent Publication <NUM>), and this definition has been generally used.

It has been said that main purposes of prevention and treatment of osteoporosis are to prevent or inhibit bone fractures, maintain the life functions and the QOL (Quality of Life), and the like. Pains caused by bone fractures and decrease in physical support functions, and subsequent life functional disorders caused by motor functional disorders are serious problems, so that it is said to particularly have a high clinical significance in the prevention and treatment of osteoporosis with a high risk of bone fractures.

Under the background described above, as a drug having the efficacies and effects for osteoporosis with a high risk of bone fractures, a daily administered preparation or a once-weekly administered preparation, each containing teriparatide or a salt thereof as an active ingredient, has been developed. After being approved for sales thereof, the preparation has been actually used in clinical situations (Non-Patent Publications <NUM> and <NUM>).

However, it is said that a daily administered preparation or a once-weekly administered preparation, each containing teriparatide or a salt thereof as an active ingredient, is not necessarily satisfactorily excellent from the viewpoint of safety.

PTH has been known to have a relaxation action of vascular smooth muscles (Non-Patent Publication <NUM>). In clinical tests using a daily administered preparation, it has been reported that dizziness is significantly high as compared to that of a placebo group (Non-Patent Publication <NUM>). In addition, it has also been known to show shocks, or unconsciousness accompanying a transient drastic blood pressure drop, convulsion, or fall, from immediately after to several hours after the administration of a daily administered preparation or a once-weekly administered preparation (Non-Patent Publications <NUM> and <NUM>).

Alternatively, it has been reported that nausea, vomiting, headaches, or the like is often observed by the administration of teriparatide acetate (Non-Patent Publication <NUM>). For example, it has been reported that in clinical tests using a once-weekly administered preparation, the nauseation frequency is significantly high, as compared to that of a placebo group, and the numerical value also exceeded <NUM>% of the entire group of the once-weekly administered preparations, and that the administration discontinuation rate due to adverse events also showed a high numerical value of about <NUM>% (Non-Patent Publication <NUM>).

Further, it has been reported that in clinical tests using a daily administered preparation, the incidence rate of a mid-level hypercalcemia (exceeding <NUM>/dl) was <NUM>% (<NUM>% in a placebo group) (Non-Patent Publication <NUM>).

Besides, in tests using a once-weekly administered preparation or a daily administered preparation, fervescence has been observed as an adverse event (Non-Patent Publications <NUM> and <NUM>).

In general, it has been reported that the drug ingestion situations in drug therapies for osteoporosis are such that <NUM>% of the individuals undesirably drop out from the ingestion within <NUM> years after the beginning of the treatment, and there are some disadvantages addressed to the lowering in the inhibition of bone fractures, the increased needs of use of facilities, and stagnancy in medical cost reductions, due to unsatisfactory compliance to drug ingestions (Non-Patent Publication <NUM>). Factors associated with the failure to the compliance to the drug ingestions are exemplified by the presence of pains, side effects, drugs ingested for gastrointestinal disorders, and the like (Non-Patent Publication <NUM>).

On the other hand, it has been pointed out that a preparation containing teriparatide or a salt thereof as an active ingredient has the lowness of the continuation rate of treatment, and it has been reported that the continuation rate of treatment over a period of <NUM> months is <NUM>% (Non-Patent Publication <NUM>). As to safety, it has been known to have the concern of the lowering in the drug ingestion adherence due to side reactions. It has been reported that in tests using a once-weekly administered preparation, adverse events that lead to the discontinuation of administration of the investigational products other than the serious cases are as high as <NUM>% in the present preparation group (Non-Patent Publication <NUM>).

As described above, a daily administered preparation or a once-weekly administered preparation, each containing teriparatide or a salt thereof as an active ingredient, shows many disadvantages in the aspects of safety, and it is also not necessarily said to provide sufficient benefits from the aspects of efficacies.

For example, it has been reported that in clinical tests having an administration period of <NUM> weeks in which a once-weekly administered preparation is used in osteoporosis patients with high risks of bone fractures, the bone mineral density of lumbar vertebrae at a time point of <NUM> weeks after the beginning of administration is elevated by <NUM> to <NUM>% or so (Patent Publication <NUM> (Table <NUM>), Non-Patent Publication <NUM> (<FIG>)). In addition, it has been reported that in clinical tests having an administration period of <NUM> months in which a once-weekly preparation is used to osteoporosis patients with high risks of bone fractures, the bone mineral density of lumbar vertebrae at the time point of <NUM> weeks after the beginning of administration is elevated by about <NUM>% (Non-Patent Publication <NUM>).

As to the efficacies regarding both the preparations, not only the effects of increasing bone mineral density but also the effects of inhibiting bone fractures have been known. For example, it has been reported that in clinical tests using a daily administered preparation, the risks of bone fractures of lumbar vertebrae are lowered by <NUM>% (Non-Patent Publication <NUM>).

In addition, it has been reported in recent year animal experiments and investigational studies that the daily administration of teriparatide shows strong bone formation-accelerating action at sites with abundant trebeculae such as centra, but on the other hand, the administration increases voids in cortical bones such as quadrupedal bones, that a possibility of having a different action to the cortical bones according to the administration frequencies has been considered even in the intermittent administration of PTH, or the like (Non-Patent Publication <NUM>). Further, it has been reported that CTX, which is one of bone resorption markers, is found to have a tendency of elevating in a dose-dependent manner, as compared to that at the beginning of administration, at <NUM> weeks after the beginning of the daily administration of teriparatide.

It has been reported from the studies in ovary-excised rats which have been widely used as osteoporosis models that bone mineral density and bone strength are increased in accordance with a weekly dosage of teriparatide (Non-Patent Publication <NUM>).

Patent Publication <NUM> discloses methods for the treatment of osteoporosis using bisphosphonates and parathyroid hormone. Patent Publication <NUM> discloses a method for transdermal administration of parathyroid hormone by iontophoresis.

An object of the present disclosure is to provide teriparatide or a salt thereof for use in treating and/or preventing osteoporosis having excellent safety and/or efficacies.

The present invention is defined in the appended claims, and it relates to teriparatide or a salt thereof for use in preventing or treating osteoporosis in a human patient, characterized in that the teriparatide or a salt thereof is administered in a unit dose of <NUM>µg at a frequency of twice a week, wherein the intervals, not including the days of administration, of administration of twice a week are a <NUM>-day interval and a <NUM>-day interval.

According to a preferred embodiment, when the number of weeks of a period administered at a frequency of twice a week is defined as n, and the number of weeks in which the intervals, not including the days of administration, of administration of twice a week out of the n weeks are a <NUM>-day interval and a <NUM>-day interval is defined as m, (m/n) × <NUM> (%) is <NUM>% or more.

According to a further preferred embodiment, the teriparatide or the salt thereof is subcutaneously administered. any one of the above [<NUM>] to [<NUM>], which is administered to an individual with one prevalent vertebral fracture.

[<NUM>] The osteoporosis therapeutic and/or prophylactic agent according to any one of the above [<NUM>] to [<NUM>], which is administered to an individual having a serum osteocalcin concentration of less than <NUM> (ng/mL).

[<NUM>] The osteoporosis therapeutic and/or prophylactic agent according to any one of the above [<NUM>] to [<NUM>], which is administered to an individual with an age <NUM> years or older.

[<NUM>] The osteoporosis therapeutic and/or prophylactic agent according to any one of the above [<NUM>] to [<NUM>], which is administered to male.

[<NUM>] The osteoporosis therapeutic and/or prophylactic agent according to any one of the above [<NUM>] to [<NUM>], which is administered to an osteoporosis patient with a high risk of bone fractures.

[<NUM>] The osteoporosis therapeutic and/or prophylactic agent according to any one of the above [<NUM>] to [<NUM>], which is administered to an osteoporosis patient with all the bone fracture risk factors of aging, prevalent bone fractures, and low bone mineral density.

[<NUM>] The osteoporosis therapeutic and/or prophylactic agent according to any one of the above [<NUM>] to [<NUM>], which is administered to an osteoporosis patient satisfying the following conditions (<NUM>) to (<NUM>):.

According to the present discloure, teriparatide or a salt for use in treating or preventing osteoporosis, with excellent safety and/or efficacies is provided.

The present disclosure shall be described in detail hereinbelow on the basis of specific embodiments.

In the present invention, human PTH(<NUM>-<NUM>) is a peptide represented by a partial amino acid sequence consisting of amino acid residues of the position <NUM> to the position <NUM> from an N-terminal side in the amino acid sequence of human PTH(<NUM>-<NUM>) which is human parathyroid hormone.

In the present disclosure, teriparatide means human PTH(<NUM>-<NUM>) in a free form. Teriparatide can also be in a salt form.

In the present disclosure, the salt of teriparatide includes any salts formed by teriparatide and one or more volatile organic acids. The volatile organic acids are exemplified by trifluoroacetic acid, formic acid, acetic acid, and the like. When teriparatide in a free form and the volatile organic acid form a salt, the ratio thereof is not particularly limited so long as the salt is formed. In particular, as the volatile organic acid, acetic acid is preferred. Specifically, the salt of teriparatide in the present disclosure is preferably exemplified by teriparatide acetate.

Teriparatide or a salt thereof can be produced by methods that themselves are known (for example, Patent Publications <NUM> to <NUM> and the like).

The unit dose of the active ingredient is exemplified as follows.

The unit dose of the active ingredient is <NUM>µg, in terms of teriparatide. When teriparatide used is an acetate, examples include the amount added with the acetate amount. For example, in a case where teriparatide pentaacetate is used, the unit dose of the active ingredient is preferably <NUM>µg, in terms of teriparatide acetate. Therefore, in the present disclosure, the phrase "teriparatide or a salt thereof. in a unit dose of <NUM>µg" means that a unit dose is an amount of <NUM>µg, in terms of teriparatide, or an amount of <NUM>µg, in terms of teriparatide acetate.

One of the features of the present disclosure is that the administration is carried out at a frequency of twice a week.

When the osteoporosis therapeutic agent or the like is administered at a frequency of twice a week, the intervals of the administration in a week can be set at <NUM>) a <NUM>-day interval and a <NUM>-day interval (a <NUM>-day interval and a <NUM>-day interval, when not including the days of administration), <NUM>) at a <NUM>-day interval and a <NUM>-day interval (a <NUM>-day interval and a <NUM>-day interval, when not including the days of administration), or <NUM>) at a <NUM>-day interval and a <NUM>-day interval (a <NUM>-day interval and a <NUM>-day interval, when not including the days of administration) (<FIG>).

According to the present disclosure, the intervals are a <NUM>-day interval and a <NUM>-day interval (a <NUM>-day interval and a <NUM>-day interval, when not including the days of administration).

An embodiment in which the intervals of administration in a week are a <NUM>-day interval and a <NUM>-day interval (a <NUM>-day interval and a <NUM>-day interval, when not including the days of administration) will be specifically described by administration schedule examples over two weeks from the initial administration. The administration of twice a week can be carried out in the week of the initial administration (week <NUM>) by administration at Day <NUM> or Day <NUM> from the date of initial administration, and subsequently, the administration of twice a week in week <NUM> can be carried out by administration at Day <NUM>, and administration at Day <NUM> or Day <NUM> (<FIG>).

The time zone for the administration is not particularly limited, and the time zone may be during the day or may be at night. When the time zone for the administration is during the day, the administration may be administration in the morning, or administration in the afternoon or evening (in the p. However, when used in combination with another therapeutic drug or basal drug (Ca, vD preparations or the like), it is more preferred that the ingestion time does not overlap with each other.

When the number of weeks of a period in which an osteoporosis therapeutic agent or the like is administered at a frequency of twice a week is defined as n, and the number of weeks out of the n weeks in which the intervals of administration of twice a week are a <NUM>-day interval and a <NUM>-day interval (a <NUM>-day interval and a <NUM>-day interval, when not including the days of administration) is defined as m, (m/n) × <NUM> (%) can be a given level or higher. The lower limit of the proportion is exemplified by <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, or <NUM>%, and the lower limit of the proportion is preferably <NUM>% or more, and more preferably <NUM>% or more.

For example, in a case where a period in which an osteoporosis therapeutic agent or the like is administered at a frequency of twice a week is <NUM> days, and the number of weeks in which the intervals of administration of twice a week are a <NUM>-day interval and a <NUM>-day interval (a <NUM>-day interval and a <NUM>-day interval, when not including the days of administration) is <NUM>, (m/n) × <NUM> defined above would be calculated to be <NUM> ÷ (<NUM> ÷ <NUM>) × <NUM>, i.e. about <NUM> (%).

The administration route is not particularly limited, and the administration can be carried out intravenously, subcutaneously, or intramuscularly. In particular, the subcutaneous administration is preferably exemplified.

The administration sites are not particularly limited, and for example, the administration can be carried out to upper arm parts, femur parts, or abdominal parts. However, in the second or subsequent administrations, it is preferable that the administration is carried out to a site at least <NUM> or so away from the previous administration site. In addition, the administration can be facilitated by pinching the surrounding of the administration site with a hand, and raising up the administration site and the surroundings thereof from the skin surface immediately before the administration.

The period of administration is not particularly limited, and the period of administration can be properly determined by the prescription of a physician in charge depending upon the patients or the like.

The lower limit of the period of administration is not particularly limited, and the period of administration is preferably exemplified by, for example, preferably <NUM> weeks or more, <NUM> weeks or more, <NUM> weeks or more, <NUM> weeks or more, <NUM> weeks or more, or <NUM> year or more. The upper limit of the period of administration is also not limited in the same manner, and the upper limit of the period of administration preferably includes, for example, within <NUM> years, within <NUM> years, within <NUM> years, or within <NUM> years.

One of the features of the present disclosure that administration is carried out for the purpose of treatment and/or prevention of osteoporosis.

The osteoporosis in the present disclosure means "a skeletal disease characterized by compromised bone strength predisposing a person to an increased risk of fracture" (Non-Patent Publication <NUM>; the definition in Consensus Conference in NIH in <NUM>), which includes both primary osteoporosis and secondary osteoporosis.

The primary osteoporosis is exemplified by involutional osteoporosis (postmenopausal osteoporosis and senile osteoporosis), and idiopathic osteoporosis (post-pregnancy osteoporosis, juvenile osteoporosis, or the like). The secondary osteoporosis is osteoporosis triggered by a specified disease, a specified drug, and other causations. The causations include specified drugs, rheumatoid arthritis, diabetes, hyperthyroidism, sexual dysfunctions, immobility, nutrition, congenital diseases, and the like. The specified drugs include, for example, steroids. The diagnostic criteria for the primary osteoporosis are well known (Non-Patent Publication <NUM>).

The osteoporosis in the present disclosure includes preferably osteoporosis with high risks of bone fractures. The osteoporosis with high risks of bone fractures may be patients with risk factors such as low bone mineral density, prevalent bone fractures, aging, and family history with bone fractures at the femoral neck parts (Non-Patent Publication <NUM>).

As mentioned above, as drugs with efficacies and effects for osteoporosis with high risks of bone fractures, a daily administered preparation or a once-weekly administered preparation, each containing teriparatide or a salt thereof as an active ingredient, has been developed. After being approved for sales thereof, the preparation has been actually used in clinical situations. In addition, as osteoporosis therapeutic agents with high risks of bone fractures, the development of human anti-sclerostin antibodies has been advanced. From these situations, one of ordinary skill in the art can easily and clearly recognize osteoporosis with high risks of bone fractures.

As a tool for assessing the absolute riskiness of bone fractures of individuals, FRAX (registered trademark) of the WHO (World Health Organization) has been known, which can calculate the incidence probability (%) of bone fractures in the future <NUM> years of the individuals. In the daily medical services, the tool can be used as a screening means for discriminating individuals with latent high risks of bone fractures in aged individuals without symptoms who are outpatients in the medical institutions.

The osteoporosis patients in the present disclosure can be osteoporosis patients with at least one or more of the risk factors for bone fractures mentioned above. The patients described above can be preferably exemplified by osteoporosis patients with three risk factors for bone fractures of aging, prevalent bone fractures, and low bone mineral density.

In addition, the osteoporosis patients in the present disclosure can be osteoporosis patients in which at least one risk factor out of the above risk factors for bone fractures satisfies specified conditions (for example, a specified threshold value or less, a specified threshold value or more, a specified numerical range, the presence or absence, or the like).

In particular, it is preferable that the osteoporosis patients in the present disclosure are osteoporosis patients with high risks of bone fractures. The osteoporosis patients with high risks of bone fractures as described above can be preferably exemplified by osteoporosis patients satisfying the following <NUM> conditions.

Here, the prevalent bone fractures include preferably prevalent vertebral bone fractures, and the number of prevalent bone fractures can be <NUM> or more and <NUM> or less. In addition, the prevalent vertebral bone fractures can be graded as prevalent vertebral bone fractures of a low-level deformation (grade <NUM>), a mid-level deformation (grade <NUM>), or a high-level deformation (grade <NUM>) (Non-Patent Publication <NUM>).

Specific examples of the grade <NUM> include low-level bone fractures in which the decrease is <NUM> to <NUM>% in the centrum height; specific examples of the grade <NUM> include mid-level bone fractures in which the decrease is <NUM> to <NUM>% in the centrum height; and specific examples of the grade <NUM> include high-level bone fractures in which the decrease is <NUM>% or more in the centrum height, respectively.

The osteoporosis patients in the present disclosure can be osteoporosis patients that are not patients satisfying at least any one out of the following six conditions:.

The patients which are considered to have high risks of the incidence of osteosarcoma include, for example, patients with Paget's disease of the bone, patients showing high alkaline phosphatase values, patients in which epiphysical line is not closed in infants or the like and juvenile individuals, and patients that took radiation therapy which are considered to affect the bones in the past.

In addition, the osteoporosis patients in the present disclosure can be osteoporosis patients that are not patients satisfying at least any one of the following five conditions.

Alternatively, the osteoporosis patients in the present disclosure can be osteoporosis patients having low-level or mid-level renal disorders. The normal renal function, renal dysfunctions, and the levels of disorders can be discriminated on the basis of the creatinine clearance. Specifically, a creatinine clearance of <NUM>/min or more can be judged as normal renal function, a creatinine clearance of <NUM>/min or more and less than <NUM>/min can be judged as a low-level renal dysfunction, and a creatinine clearance of <NUM>/min or more and less than <NUM>/min can be judged as a mid-level renal dysfunction. The method for calculating a creatinine clearance includes, for example, the formulas of Cockcroft-Gault (male: (<NUM> - age) × body weight / (<NUM> × serum creatinine value), female: <NUM> × (<NUM> - age) × body weight / (<NUM> × serum creatinine value)) as an example.

In addition, the osteoporosis patients in the present disclosure can be osteoporosis patients that satisfy such that each of the factors respectively has specified conditions (for example, a specified threshold value or less, a specified threshold value or more, a specified numerical range, the kinds, the presence or absence, or the like), with respect to at least any one of the factors out of the following <NUM> factors which the patients have:.

For example, the osteoporosis patients in the present disclosure can be male or female patients; patients of age <NUM> years or older and younger than <NUM> years; patients of age <NUM> years or older and younger than <NUM> years; patients of age <NUM> years or older; patients with a bone mineral density of lumbar vertebrae (value calculated as YAM) (%) of less than <NUM>%, those of <NUM>% or more and less than <NUM>%, or those of <NUM>% or more and less than <NUM>%; patients with the number of prevalent vertebral bone fractures of zero; patients with the number of prevalent vertebral bone fracture of one; patients with the number of prevalent vertebral bone fractures of two to three; patients with the number of prevalent vertebral bone fractures of four to five; patients with the number of prevalent vertebral bone fractures of six or more, or the like.

The osteoporosis patients in the present disclosure are osteoporosis patients in which each of the items of at least any one of items out of the following <NUM> investigational study items respectively satisfies specified conditions (for example, a specified threshold value or less, a specified threshold value or more, a specified numerical range, or the like).

AST (GOT) as used herein means aspartate aminotransferase (glutamic-oxaloacetic transaminase)), and ALT (GPT) as used herein means alanine aminotransferase (glutamic-pyruvic transaminase)). Here, CPK as used herein means creatinine phosphokinase.

In addition, the osteoporosis patients in the present disclosure can be osteoporosis patients in which each of the items of at least any one of items out of the vital sign items (sitting systolic blood pressure, sitting diastolic blood pressure, pulse rate, and the like) respectively satisfies specified conditions (for example, a specified threshold value or less, a specified threshold value or more, a specified numerical range, or the like).

Alternatively, the osteoporosis patients in the present disclosure can also be osteoporosis patients which are capable of producing anti-drug antibodies (for example, antibodies against teriparatide or a salt thereof, and the like) and neutralizing antibodies (for example, antibodies capable of lowering or losing the activity of teriparatide or a salt thereof, and the like), with the ingestion of the osteoporosis therapeutic and/or prophylactic agent of the present disclosure.

In addition, the osteoporosis patients in the present disclosure can be osteoporosis patients in which each of the markers of at least any one of the markers out of the following <NUM> markers respectively satisfies specified conditions (for example, a specified threshold value or less, a specified threshold value or more, a specified numerical range, or the like).

P1NP as used herein means procollagen type I amino-terminal propeptide, NTX as used herein means crosslinked N-telopeptide of type I collagen, and CTX as used herein means type I collagen crosslinked C-telopeptide, respectively.

The osteoporosis patients in the present disclosure include patients with a blood osteocalcin concentration of less than <NUM> (ng/mL), patients with a blood osteocalcin concentration of <NUM> (ng/mL) or more and less than <NUM> (ng/mL), and patients with a blood osteocalcin concentration of <NUM> (ng/mL) or more.

Alternatively, the osteoporosis patients in the present disclosure include, for example, a blood osteocalcin concentration of less than <NUM> (ng/mL), patients with a blood osteocalcin concentration of <NUM> (ng/mL) or more and less than <NUM> (ng/mL), and patients with a blood osteocalcin concentration of <NUM> (ng/mL) or more.

In addition, the osteoporosis patients in the present disclosure include, for example, patients with a blood P1NP concentration of less than <NUM> (µg/L), patients with a blood P1NP concentration of <NUM> (µg/L) or more and less than <NUM> (µg/L), and patients with those of <NUM> (µg/L) or more.

Alternatively, the osteoporosis patients in the present disclosure include, for example, patients with a blood P1NP concentration of less than <NUM> (µg/L), patients with a blood P1NP concentration of <NUM> (µg/L) or more and less than <NUM> (µg/L), and patients with those of <NUM> (µg/L) or more.

The osteoporosis patients in the present disclosure can also be patients having therapeutic history with previous therapeutic drugs for osteoporosis. The previous therapeutic drugs for osteoporosis include calcium drugs, female hormone drugs, SERMs (selective estrogen receptor modulators), active vitamin D<NUM> drugs, vitamin K<NUM> drugs, calcitonin drugs, parathyroid hormone drugs, bisphosphonate drugs, and denosumab.

Here, the SERMs are preferably exemplified by raloxifene and bazedoxifene; the active vitamin D<NUM> drugs are preferably exemplified by eldecalcitol, alfacalcidol, and calcitriol; and the vitamin K<NUM> drugs are preferably exemplified by menatetrenone, respectively. Further, the bisphosphonate drugs are exemplified by etidronate, alendronate, risedronate, minodronate, and ibandronate. The calcitonin drugs are exemplified by calcitonin salmon and elcatonin. The parathyroid hormone drugs include a daily administered preparation or a once-weekly administered preparation, containing teriparatide or a salt thereof mentioned above as an active ingredient.

In addition, the osteoporosis patients in the present disclosure can be osteoporosis patients suffering from other diseases, in other words, osteoporosis patients having complications. Other diseases include diabetes, hypertension, adipogenetic aberrancy (hyperlipemia or the like), chronic kidney diseases (CKD), rheumatoid arthritis, gout, hyperuricemia, dementia, cataract, senile hearing impairments, dysuria, cerebrovascular diseases, ischemic cardiac diseases, and the like.

Alternatively, the osteoporosis patients in the present disclosure can also be osteoporosis patients who are in a care-needed state.

The osteoporosis therapeutic and/or prophylactic agent can be used in combination with other drugs. Other drugs can be administered in the identical or different routes, simultaneously or successively (i.e., at separate time) with the osteoporosis therapeutic and/or prophylactic agent.

Other drugs include at least one of the drugs in the previous therapeutic drugs for osteoporosis mentioned above. Alternatively, other drugs also include a therapeutic and/or prophylactic agent for complications mentioned above. In addition, other drugs may be a basal drug (Ca, vD preparations, and the like).

Preferred basal drugs include vD<NUM> (vitamin D<NUM>) preparations, magnesium preparations, and calcium preparations. These basal drugs can be used together in any combinations, and they may be in the form of a combination preparation. For example, calcium preparations formulated with vD<NUM> and magnesium are preferably exemplified as a basal drug. The combination preparation as described above is preferably ingested once a day after an evening meal, the combination preparation containing vD<NUM> 400IU, magnesium <NUM>, and calcium <NUM> per dose.

When the osteoporosis therapeutic and/or prophylactic agent is subjected to a clinical test as a test drug, the evaluation can also be carried out in the state that the test individuals are ingested with the above or equivalent basal drug (Non-Patent Publication <NUM>). Here, the considerations can be made to the ideas that the decrease in the risks of bone fractures by a combined use of vD and a calcium preparation is indefinite (Non-Patent Publication <NUM>), and that when both the test drug group and the control drug group are given with a basal drug, the influences of the basal drug in the differences between the two groups on efficacies and safety are not probably substantially recognized. In view of these ideas, when the osteoporosis therapeutic and/or prophylactic agent is used in a clinically practiced site, the use of vD and a calcium preparation is not necessarily needed.

The osteoporosis therapeutic and/or prophylactic agent can take various preparation forms. In general, it is preferable that the preparation is in the form of an injection containing pharmaceutically acceptable excipients and additives, from the viewpoint of safety or the like.

The excipients and the additives are not particularly limited, including, for example, a sugar alcohol (mannitol or the like), an inorganic salt (sodium chloride or the like), a saccharide (sucrose or the like), or an amino acid (methionine or the like). The preparation may contain a buffer, or may not contain a buffer. The pH of the preparation can be appropriately adjusted, and the pH can be adjusted to, for example, from <NUM> to <NUM>.

The concentration of the active ingredient in the preparation is also not particularly limited, and the concentration can be, for example, <NUM>µg/mL or more, and can also be from <NUM> to <NUM>µg/mL.

When the preparation is in the form of an injection, the preparation can be produced by dissolving an active ingredient, excipients and additives in a proper solvent (sterile water, a buffer, physiological saline or the like), subjecting the solution to filtration with a filter or the like and/or sterile treatment, and subsequently dispensing and sealing the filtrate in a container previously cleaned and subjected to sterile treatment.

Here, examples of the dispensing container include, for example, ampules, vials, pre-filled syringes, bags, and the like. The materials for the container include, but not particularly limited to, glass and plastics. The materials for the container are preferably exemplified by plastics, from the viewpoint of strength, easiness in handling, safety, and the like.

For example, the preparation may be an automatically administered preparation in which a pre-filled syringe with a needle which is previously dispensed with a drug solution is incorporated into an auto-injector. Since the osteoporosis therapeutic agent or the like shows sufficient safety, the preparation can serve as an automatically administered preparation for domiciliary care.

The main purpose of the present disclosure is to prevent or inhibit bone fractures.

The bone fractures in the present disclosure include pathological bone fractures caused by osteoporosis, osteogenesis imperfecta, bone tumor, or the like, and traumatic bone fractures caused by traffic accidents, bruises, or the like. The bone fractures preferably include bone fractures caused by osteoporosis.

The bone fractures in the present disclosure include both vertebral bone fractures and non-vertebral bone fractures. The non-vertebral bone fractures include, but also not particularly limited to, for example, bone fractures in the proximal part of the femur, the distal end of the radius, the proximal part of the humerus, the tibiae, pelvis, costa, and the like. The bone fractures in the present disclosure preferably include vertebral bone fractures (new vertebral bone fractures, worsening vertebral bone fractures, and the like).

In general, the femoral proximal fractures mean hip fractures of elderly individuals, which are understood to be bone fractures that are different from the fractures of the proximal part of the femur (Non-Patent Publication <NUM>). The bone fractures that are included in the femoral proximal fractures include, for example, subchondral insufficiency fracture of the femoral head, femoral neck fracture, basal neck fracture of the femur, trochanteric fracture of the femur, and subtrochanteric fracture of the femur (Non-Patent Publication <NUM>).

Here, since the subchondral insufficiency fracture of the femoral head is very rare and the diagnosis of the basal neck fracture of the femur is difficult, they can also be classified into either one of femoral neck fracture and trochanteric fracture of the femur. Since the distinctions between the trochanteric fracture of the femur and the subtrochanteric fracture of the femur are not clear, it is also possible to employ a method of roughly classifying the femoral proximal fractures into two groups of the femoral neck fracture and the trochanteric fracture of the femur (Non-Patent Publication <NUM>). The femoral proximal part may be also referred to a femoral proximal total, from the implications of emphasizing its totality.

The vertebral bone fractures have a very high clinical significance in the prevention or inhibition thereof because the vertebral bone fractures are osteoporosis bone fractures with the highest frequency and the vertebral bone fractures are important as an index for diagnosis and treatment of osteoporosis (Non-Patent Publication <NUM>). In addition, since the femoral proximal fractures cause the worsening of life functions or the QOL and the femoral proximal fractures are considered to also be relevant to life prognosis (Non-Patent Publication <NUM>), it is preferable that measures for sufficient prevention or inhibition are taken against the femoral proximal fractures.

The vertebral bone fractures can be judged as morphometric bone fractures according to the level of degree of deformation of vertebrae irrelevant to the presence or absence of clinical symptoms (Non-Patent Publication <NUM>). The morphometric bone fractures can be classified into prevalent bone fractures and new bone fractures.

The new bone fractures can be defined as bone fractures which are judged as new incidence by comparing X-ray images or the like at two time points, and the prevalent bone fractures can be bone fractures which are judged by the extent of deformation of the centrum at one time point before the beginning of the treatment. Of the new bone fractures, those in which the centrum that has not undergone deformation before the beginning of the treatment is deformed after the beginning of the treatment are defined as new vertebral bone fractures, which can also be distinguished from worsening bone fractures that are those in which the extent of deformation of the centrum is increased after the beginning of the treatment. The new vertebral bone fractures and the worsening vertebral bone fractures as used herein are expressed in the distinctions as mentioned above.

The vertebral bone fractures in the present disclosure include both new vertebral bone fractures and worsening vertebral bone fractures. For example, the extent of the deformation of the centrum can be classified according to Grades in view of the forms of the total centrum, which is generally classified as Grade <NUM> (normal), Grade <NUM> (decrease of about <NUM> to about <NUM>% in the centrum height, and decrease of <NUM> to <NUM>% in the centrum area), Grade <NUM> (decrease of about <NUM> to about <NUM>% in the centrum height, and decrease of <NUM> to <NUM>% in the centrum area), and Grade <NUM> (decrease of about <NUM>% or more in the centrum height, and decrease of <NUM>% or more in the centrum area). The distinctions of new and worsening can be carried out in line with the increase patterns of Grade in accordance with the judgment criteria of Genant. Specifically, in cases where a change is found from Grade <NUM> to Grade <NUM>, <NUM>, or <NUM>, it is diagnosed as a new vertebral bone fracture, and in a case where a change is found from Grade <NUM> to Grade <NUM> or <NUM>, or from Grade <NUM> to Grade <NUM>, it can be considered as a worsening bone fracture.

Of the bone fractures in the present disclosure bone fractures which are diagnosed with clinical symptoms such as pains can be referred to as clinical bone fractures, and the clinical bone fractures can be classified into clinical vertebral bone fractures and clinical non-vertebral bone fractures. The clinical non-vertebral bone fractures as used herein are simply referred to as non-vertebral bone fractures. The clinical symptoms are, for example, acute pains of dorsolumbar parts, and the like, which can be confirmed by appeals made by the test individuals.

The bone fracture assessment method using an X-ray image or MRI is a method that itself is known, and, for example, a quantitative assessment method (QM method) or a semi-quantitative assessment method (SQ method) has been known. The SQ method is a method proposed by Genant et al. in <NUM>, which has been so far used in many clinical tests in Japan or elsewhere, and the evidences thereof have been constructed, so that the method can be more preferably used (Non-Patent Publication <NUM>). Besides them, a method by Wu et al. or a method by Fukunaga et al. can also be used (Non-Patent Publications <NUM> to <NUM>).

When the osteoporosis therapeutic and/or prophylactic agent is tested, it is preferable that the bone fracture inhibitory action thereof is assessed. When the bone fracture inhibitory action of a test drug is assessed, the bone fracture inhibitory action (bone fracture risk reducing property or the like) of the test drug can be also assessed in the same test without using a placebo control drug in the same test by subjecting a control drug which is found to have bone fracture inhibitory property by past clinical data or the like to a test and carrying out the same test to obtain a bone fracture incidence rate of the control drug, and comparing a bone fracture incidence rate of a test drug with a bone fracture incidence rate of a control drug, or by comparing a bone fracture incidence rate of a test drug with a bone fracture incidence rate without treatment for test individuals of the same test which can be assumed on the basis of the past clinical data or the like.

The bone strength is made up of two factors, bone mineral density and bone quality, and in general, the "bone mineral density" can account for about <NUM>% of the bone strength, and the "bone quality" can account for the remaining <NUM>% or so (Non-Patent Publication <NUM>). Even in a daily administered preparation or a once-weekly administered preparation, the preparation containing teriparatide or a salt thereof as an active ingredient, not only the bone fracture inhibitory effects but also bone mineral density increasing effects have been known (Non-Patent Publications <NUM>, <NUM>, <NUM>, and <NUM>).

Here, the bone mineral density refers typically to a bone mineral content of the lumbar vertebrae. The lumbar vertebrae are rich in trabecular bones having a fast bone turnover, so that the sensitivity of a detection change of the change in bone mineral densities by a drug therapy is also high. In addition, in a case where the assessment of the bone mineral content of the lumbar vertebrae is difficult or the like, the bone mineral density can be expressed by the bone mineral content values of the radius, the second metacarpal bone, the femoral neck part, or the calcaneus. In addition, the young adult mean infers to a mean value of bone mineral densities of ages <NUM> to <NUM> years.

The bone mineral density can be measured by methods that are themselves known, for example, dual-energy X-ray absorptiometry, photodensitometry, photon absorptiometry, quantitative CT scan, quantitative ultrasonography, and the like.

The change rate in bone mineral densities can be calculated by, for example, the following formula: <MAT>.

In addition, the degree of bone atrophy in the present disclosure means a degree of loss in bone mass on an X-ray. The degree of bone atrophy is classified into no bone atrophy, bone atrophy grade I, bone atrophy grade II, and bone atrophy grade III. No bone atrophy in the degree of bone atrophy refers to a normal condition, which specifically means a condition in which the trabecular structure cannot be recognized because latitudinal and longitudinal trabeculae are dense. Bone atrophy grade I means that longitudinal trabeculae are prominent. Typically, it means a condition in which the longitudinal trabeculae are thin and visible but still arranged densely, and the end plates of the centrum are prominent. Bone atrophy grade II in the degree of bone atrophy means a state in which the longitudinal trabeculae have become rough, appear thick, and are roughly arranged, and the end plates of the centrum also have lighter color. Bone atrophy grade III in the degree of bone atrophy means a condition in which the longitudinal trabeculae become indistinct, the centrum shadows appear blurry as a whole, and the difference from the shadows of the intervertebral disks is reduced. The degree of bone atrophy can be judged, for example, from a lateral X-ray image of the lumbar vertebrae.

The fluctuations in the bone metabolism markers are associated with the prevention or inhibition of bone fractures and increase in bone mineral densities. Therefore, when the osteoporosis therapeutic agent is assessed or the like from the aspect of efficacies, it is considered to be useful to measure bone metabolism marker values in biological samples (blood samples, urine samples, and the like) derived from test individuals, and confirm the fluctuations thereof (for example, differences between values before the administration and values after the administration) (Non-Patent Publication <NUM>).

For the purpose of assessing the osteoporosis therapeutic and/or prophylactic agent in the aspect of efficacies, the fluctuations of bone metabolism markers, the increase in bone mineral densities, or the inhibition of bone fractures can be observed. In an administration embodiment where a method of administration is twice a week in the present disclosure in which the intervals of the administration in a week are a <NUM>-day interval and a <NUM>-day interval (not including the days of administration), it is preferable that the efficacies are assessed by directly observing the increase in bone mineral densities or the inhibition of bone fractures.

The bone metabolism markers are roughly classified into bone formation markers and bone resorption markers. The bone formation markers can be substances that are directly or indirectly produced from osteoblasts at each stage of differentiation of the osteoblasts, and osteocalcin, P1NP or the like has been known. The bone resorption markers can be substances that are related to activation or bone resorption of osteoclasts, and NTX, CTX or the like has been known.

Conventionally, regarding a daily osteoporosis therapy using teriparatide, particularly at an early stage, the dissociation of the bone formation markers which are found to have a rapid increase from the beginning of administration and the bone resorption markers is called "anabolic window," which has been considered to the mechanism of increase in bone mineral densities from an early stage of administration (Non-Patent Publication <NUM>). Also in the osteoporosis therapeutic and/or prophylactic agent, the fluctuations of the bone metabolism markers, for example, "Anabolic window" can serve as an index for therapeutic monitoring particularly at an early stage of the beginning of administration (for example, within several months from the beginning of administration).

However, the administration embodiment where a method of administration of twice a week in the present disclosure in which the intervals of the administration in a week are a <NUM>-day interval and a <NUM>-day interval (not including the days of administration) can be clearly distinguished from the conventional teriparatide therapeutic method with regard to the relationship between the bone metabolism markers and the efficacies. Therefore, when the efficacies are assessed in the same administration embodiment, it is more preferable that the increase in bone mineral densities or the inhibition of bone fractures is directly observed, not the fluctuations of the bone metabolism markers.

Further, according to the studies on rats subjected to ovariectomy which are widely used as osteoporosis models (Non-Patent Publications <NUM> and <NUM>), it has been reported that the voids in the cortical bone are increased according to the dosage when the dosage frequency of teriparatide is high (Non-Patent Publication <NUM>).

In addition, it has been reported that teriparatide has been used as a therapeutic agent for osteoporosis with a high risk of bone fractures, and the voids in the cortical bone are increased in the subject patients by aging or pathologies, and it has been reported that the therapeutic strategies in considerations of pathologies of the patients and the features of the pharmacological actions of teriparatide are needed in order to maximize the therapeutic effects with teriparatide (Non-Patent Publication <NUM>).

Therefore, in the treatment or prevention in the present disclosure, an embodiment such that a blood concentration or a urine concentration of the bone resorption markers which are deeply related with the void formation or porosity in the cortical bone is reduced with the time course or the increase is inhibited with the time course, while increasing the bone formation markers associated with an increase in bone mineral densities and a bone fracture inhibitory rate is preferred. The bone resorption markers which are deeply related with the void formation or porosity in the cortical bone can be exemplified by NTX and CTX. Moreover, an embodiment of the present disclosure as described above can be an embodiment in which the intervals between administrations are appropriately taken so as not to continuously increase bone resorption when repeatedly administered. More specifically, for example, the treatment or prevention in which a dosage is <NUM>µg, in terms of teriparatide, is exemplified, among which a method of administration twice a week in the present disclosure (provided that a unit dose is <NUM>µg in terms of teriparatide), in which the intervals of administration in a week are a <NUM>-day interval and a <NUM>-day interval (not including the days of administration), is preferably exemplified.

All the unwanted or unintended diseases or symptoms thereof caused in individuals administered with a drug can be referred to as adverse events (AE).

Among the adverse events, those in which cause-and-effect relationship with a drug cannot be denied can be referred to as side effects. The matter that the cause-and-effect relationship cannot be denied includes the matter that a reasonable possibility of the cause-and-effect relationship is found, and the matter that no reasonable possibilities of the cause-and-effect relationship cannot be assessed.

The adverse events can be roughly classified into serious adverse events and non-serious adverse events, and the following six adverse events can be defined as serious adverse events, and the adverse events other than the serious adverse events can be defined as non-serious adverse events.

In addition, in addition to the seriousness and the cause-and-effect relationships, the adverse events can be roughly classified by the levels of the adverse events. For example, the following three levels can be considered.

Alternatively, the adverse events can also be classified in terms of the outcomes of treatment as, for example, being recovered/resolved, recovering/resolving, being not recovered/not resolved, being recovered/resolved with sequelae, being dead, and unknown, from the viewpoint of changes in the time course.

The method when a certain drug is compared with a different drug in safety is not particularly limited. For example, a certain adverse event is remarked, and the comparisons can be made with respect to expression frequency, seriousness, cause-and-effect relationship, the outcomes of treatment, and/or levels. Alternatively, both the drugs can be compared from the viewpoint of administration discontinuation caused by the entire or a part of the adverse events or the entire or part of the side effects.

The adverse events can include abnormality in clinical test values and vital signs.

The adverse events are not particularly limited, and can be classified according to the System Organ Class (SOC). The System Organ Class in connection with the adverse events is exemplified by the following.

The adverse events classified as the "infections and infestations" can be exemplified by epipharingitis and influenza. The adverse events classified as the "nervous system disorders" can be exemplified by headaches and free-floating dizziness. The adverse events classified as the "respiratory, thoracic and mediastinal disorders" can be exemplified by inflammations in the upper airway. The adverse events classified as the "gastrointestinal disorders" can be exemplified by nausea, vomiting, constipation, or the like. The adverse events classified as the "skin and subcutaneous tissue disorders" can be exemplified by eczema. The adverse events classified as the "musculoskeletal and connective tissue disorders" can be exemplified by osteoarthritis. The adverse events classified as the "general and systemic disorders and administration site conditions" can be exemplified by malaise, bleeding at injected sites, and fervescence. The adverse events classified as the "injury, poisoning and procedural complications" can be exemplified by contusion.

As mentioned above, it has been also reported that nausea, vomiting, headaches, or the like is often observed by the administration of teriparatide acetate (Non-Patent Publication <NUM>). In addition, in clinical tests using a daily administered preparation containing teriparatide or a salt as an active ingredient, it has been reported that dizziness is significantly high as compared to that of the placebo group (Non-Patent Publication <NUM>). Further, it has also known to show shocks, or unconsciousness or the like accompanying a transient drastic blood pressure drop, from immediately after the administration to several hours of a daily administered preparation or a once-weekly administered preparation, each containing teriparatide or a salt thereof as an active ingredient (Non-Patent Publications <NUM> and <NUM>).

Therefore, in the treatment or prevention in the present disclosure, an embodiment in which the expression frequency, the seriousness, and/or the levels of at least any one of the adverse effects or side effects out of adverse events or side effects such as nausea, vomiting, headaches, or the like, (free-floating) dizziness, shocks, a pressure drop, or unconsciousness is inhibited as much as possible is preferred.

As mentioned above, in general, it has been reported that the drug ingestion situations in drug therapies for osteoporosis are such that <NUM>% of the individuals undesirably drop out from the ingestion within <NUM> years after the beginning of the treatment, and there are some disadvantages addressed to the lowering in the inhibition of bone fractures, the increase in needs of use of facilities, and stagnancy in medical cost reductions due to lack of compliance to drug ingestions (Non-Patent Publication <NUM>). Factors associated with the failure to the compliance to the drug ingestions are exemplified by the presence of pains, side effects, drugs ingested for gastrointestinal disorders, and the like (Non-Patent Publication <NUM>). On the other hand, the preparation containing teriparatide or a salt thereof as an active ingredient has been addressed in the lowness in the therapeutic continuality, and it has been reported that the therapeutic continuality rate over a period of <NUM> months is <NUM>% (Non-Patent Publication <NUM>).

Therefore, providing a drug therapy with teriparatide or a salt thereof, the therapy exhibiting an even higher therapeutic continuality rate is considered to have a publicly high significance in social welfare and medicinal economy beyond the living improvements in the individual patients.

In view of the above, in the treatment or prevention in the present disclosure, an embodiment showing a high therapeutic continuality rate is preferred.

Test individuals were randomly assigned to either one of Test Drug Group and Control Drug Group. As shown in <FIG>, each test individual of Test Drug Group was subcutaneously administered with a test drug and a control drug placebo, and each test individual of Control Drug Group was subcutaneously administered with a control drug and a test drug placebo, over <NUM> weeks in accordance with a double blind method (a double dummy method). In addition, the test individuals of both the groups ingested two tablets of a standard concomitant drug at a frequency of once a day after an evening meal.

In a case where each test individual uses an osteoporosis therapeutic agent within <NUM> weeks before the obtainment of the consent for the investigational studies, those test individuals were subjected to a washout. Upon washout, the following day of a final ingestion or the day of injection of the previous therapeutic agent for the treatment of osteoporosis is defined as Day <NUM> of washout, and it is considered to be acceptable if the beginning day of the investigational studies with the investigational product is on or after <NUM> weeks (<NUM> days) of the washout. However, as a general rule, the beginning of the treatment with an investigational product did not exceed <NUM> weeks (<NUM> days) from the obtainment of the consent.

When a physician in charge of the investigational studies or a contributory physician of the investigational studies discontinued the investigational studies for the test individuals when it was acknowledged that test individuals met given criteria after the beginning of the treatment with an investigational product. The given criteria were adverse events, lack of effects, impossibility of tracking studies, judgments by the physician in charge of the investigational studies or the contributory physician of the investigational studies, serious departure from the protocol of the investigational studies, compliance failures to the administration of an investigational product, proffers by test individuals, or judgments of the individuals that requested for the investigational studies.

A test drug was an auto-injector preparation containing <NUM> of a drug solution in one shot, and when an entire amount of a single shot of the preparation was administered, <NUM>µg in terms of teriparatide (<NUM>µg in terms of teriparatide acetate) was administered. The drug solution is previously filled in a prefilled syringe with a needle incorporated in the auto-injector, the auto-injector being a tool used in subcutaneous injection of a drug solution to human bodies.

A test drug placebo is an auto-injector preparation which is not distinguishable in external comparison from a test drug, the preparation not substantially containing teriparatide.

A control drug is a vial preparation, which is a freeze-dried preparation for injection containing <NUM>µg in terms of teriparatide (<NUM>µg in terms of teriparatide acetate) in one vial. Here, a control drug is a preparation with which <NUM>µg in terms of teriparatide is administered, when a drug solution obtained by adding <NUM> of Japanese Pharmacopoeia physiological saline to the drug to dissolve is administered with a syringe.

A control drug placebo is a freeze dried preparation for injection which is not distinguishable in external comparison from a test drug, the preparation not substantially containing teriparatide.

A standard concomitant drug is a calcium preparation formulated with vitamin D<NUM> and magnesium (New CALCICHEW (registered trademark) D<NUM>; manufactured and sold by Nitto Pharmaceutical Industries, Ltd. , and sold by Takeda Pharmaceuticals Company, Limited). Two tablets of the standard concomitant drug contain precipitated calcium carbonate <NUM>,<NUM> (<NUM>, in terms of calcium), magnesium carbonate <NUM> (<NUM>, in terms of magnesium), cholecalciferol <NUM> IU (vitamin D<NUM>), and various additives.

The intervals of administration at a frequency of twice a week are, in principle, three-day to four-day-intervals (two day- or three day-intervals between administrations). The intervals of administration (three day- or four day-interval) in principle as used herein mean that when the day of administration of either one of administration out of the two consecutive administrations was defined as Day <NUM>, the day of the other administration was Day <NUM> or Day <NUM>. For example, when administered on Monday of a certain week, the next day of administration would be, in principle, on Thursday or Friday, as shown below.

Test individuals were osteoporosis patients with all of the three bone fracture risk factors of "aging," "prevalent bone fractures," and "low bone mineral density. " More specifically, test individuals were patients with primary osteoporosis that satisfied all the following conditions (<NUM>) to (<NUM>) (satisfying the selected criteria), but did not satisfy any one of the following conditions (<NUM>) to (<NUM>) (satisfying the exclusion criteria). Since the test individuals are osteoporosis patients with all of the three bone fracture risk factors of "aging," "prevalent bone fractures," and "low bone mineral density" (satisfying the following conditions (<NUM>) to (<NUM>)), the test individuals are osteoporosis patients with high risks of bone fractures.

Here, the "bone assessment committee members" refer to committee members which constitute "the bone assessment committee" which has been founded for the purpose of equally assessing the assessment of bone mass and the assessment of bone fractures of all the patients. Each of the assessment committee members is constituted by experts of imaging diagnosis for osteoporosis.

Each patient assigned to Test Drug Group was subcutaneously injected with a single shot of a test drug twice a week (self-injected at any one of sites of upper arm parts, femur parts, and abdominal parts). The intervals of administration in a general rule were three to four days (two day- or three day-intervals between administrations). Further, the same patients were subcutaneously injected once a week (injected upon visits to medical institutions) with a solution obtained by dissolving one vial of a control drug placebo in <NUM> of Japanese Pharmacopoeia physiological saline upon use.

Each patient assigned to Control Drug Group was subcutaneously injected with a single shot of a test drug placebo twice a week (self-injected at any one of sites of upper arm parts, femur parts, and abdominal parts). Further, the same patients were subcutaneously injected once a week (injected upon visits to medical institutions) with a solution obtained by dissolving one vial of a control drug in <NUM> of Japanese Pharmacopoeia physiological saline upon use.

The main assessment item for the efficacies of the test was a change rate in bone mineral densities of lumbar vertebrae (second to fourth lumbar vertebrae).

The subsidiary assessment items for the efficacies of the test were a change rate in femoral bone mineral densities, a change rate in bone mineral densities of lumbar vertebrae (first to fourth lumbar vertebrae), an incidence rate of new vertebral bone fractures, an incidence rate of worsening vertebral bone fractures, incidence rates of (new and worsening) vertebral bone fractures, incidence rates of clinical bone fractures (clinical vertebral bone fractures and non-vertebral bone fractures), an incidence rate of vulnerable clinical bone fractures, an incidence rate of vulnerable non-vertebral bone fractures, and bone metabolism markers.

The safety assessment items for the test were adverse events, vital signs, clinical tests, and immunogenicity.

The methods for measuring each of change rates in bone mineral densities of the bone mineral densities of lumbar vertebrae and the femoral bone mineral densities are shown in the following Table <NUM>-<NUM>.

The methods for assessing vertebral bone fractures are shown in the following Table <NUM>-<NUM>.

In a case where the test individuals appealed (for clinical symptoms) up to <NUM> weeks (at discontinuation) after the beginning of treatment and a physician in charge of the investigational studies or a contributory physician of the investigational studies confirmed the bone fractures by an X-ray photograph, MRI or the like, the test individuals were diagnosed as clinical bone fractures. In particular, in a case where test individuals appealed for acute pains at the lower back parts or back parts, an X-ray photograph was taken to confirm the presence or absence of the bone fractures.

The contents of assessment were the incidence date of bone fractures (the day a test individual developed the clinical symptoms), bone fracture sites (the centrum, femoral proximal parts, radius, upper arm bone, and others), the presence or absence of a large external force, the bases of judgment for the bone fractures (X-ray photographing, MRI, the information from other service departments or other medical institutions, and others), and the date of photographing X-ray or MRI.

The methods for testing bone metabolism markers are shown in the following Table <NUM>-<NUM>.

A physician in charge of the investigational studies or a contributory physician of the investigational studies studied on adverse events by voluntary reports from the test individuals, diagnosis by physician's inquiries on conditions of patients, and various tests, over a period from the day of the obtainment of the consent from each test individual to one week after the final day of administration.

The study items were the name of adverse events, the incidence date, the situations of administration of an investigational product, the day of disappearance, the outcomes of treatment, the classifications of degrees of seriousness, the reasons of seriousness, the levels, the cause-and-effect relationships between the investigational product and a standard concomitant drug, and when the adverse events were caused in the injected sites, the sites thereof, and the presence or absence of the discontinuation of the investigational studies.

The methods for measuring vital signs are shown in the following Table <NUM>-<NUM>.

The method for a clinical test is shown in the following Table <NUM>-<NUM>.

A physician in charge of the investigational studies or a contributory physician of the investigational studies collected analytes (blood) before the administration of an investigational product on the day of each test, and stored. An anti-drug antibody against the investigational product was measured after the collection of analytes. Only those analytes in which the anti-drug antibody was positive were measured for a neutralizing antibody.

Test individuals that expressed the consent of the treatment were <NUM> people, out of which <NUM> people registered for the investigational studies and received the treatment, in which <NUM> people discontinued the treatment and <NUM> people completed the treatment. Of those <NUM> people that received the treatment, the backgrounds (outline) of <NUM> people which were subjects to be analyzed for the efficacies are shown in the following Table <NUM>-<NUM>. Table <NUM>-<NUM> shows that there are no large imbalances in backgrounds between Test Drug Group and Control Drug Group, so that the risks of bone fractures would be probably nearly of the same level.

The mean of the number of administrations and the mean of the administration period in <NUM> individuals who received treatment are shown in Tables <NUM>-<NUM> and <NUM>-<NUM>. Here, as to the mean of the number of administrations, a tested individuals that were previously administered with a test drug as an actual drug (MN-<NUM>-T AI) were administered with a control drug placebo (MN-<NUM>-T Placebo), and test individuals that were previously administered with a control drug as an actual drug (MN-<NUM>-T) were administered with a test drug placebo (MN-<NUM>-T AI Placebo) (<FIG>). Therefore, the mean of the number of administrations of the four agents, a test drug actual drug, a control drug placebo, a test drug placebo, and a control drug actual drug, is calculated.

It was considered that there were no significant differences in the mean of the number of administrations when the test drug actual drug of Test Drug Group was compared with the test drug placebo of Control Drug Group, and the control drug placebo of Test Drug Group was compared with the control drug actual drug of Control Drug Group.

It was considered that there were no differences in the mean of the administration period between Test Drug Group and Control Drug Group. Here, the reasons why some did not reach <NUM> weeks are in that examples that were discontinued in the course were included.

The time transitions of the mean value of a change rate in bone mineral densities of each of lumbar vertebrae (second to fourth lumbar vertebrae), lumbar vertebrae (first to fourth lumbar vertebrae), a femoral neck part, and a femoral proximal total in the subjects to be analyzed for the efficacies are shown in the following Tables <NUM>-<NUM> to <NUM>-<NUM>. The numerical values in the tables show a mean value of a change rate (%) from the beginning.

In addition, the time transitions of the mean value of a change rate in bone mineral densities of lumbar vertebrae (second to fourth lumbar vertebrae) in the subjects to be analyzed for the efficacies are shown in <FIG>.

The treatment with a test drug showed high increase rates in all of the bone mineral density of lumbar vertebrae, the bone mineral density of the femoral neck part, and the bone mineral density of femoral proximal total, as compared to those treatment with a control drug. Especially, it was significantly high in the bone mineral densities of lumbar vertebrae.

When the treatment with a test drug was compared with the treatment with a control drug, it is considered that the dosage of teriparatide per week is substantially of the same level. On the other hand, it has been reported that the bone mineral density and the bone strength increase in accordance with the dosage of teriparatide per week (Non-Patent Publication <NUM>). Therefore, it was considered that the results which can be thought to be significant in the comparisons between the treatment with a test drug and the treatment with a control drug can be clearly distinguished from the conventional medical techniques.

The subjects to be analyzed for the efficacies were divided into subgroups in which the bone mineral densities of lumbar vertebrae (second to fourth lumbar vertebrae) at the beginning or the number of prevalent vertebral bone fractures was used as an index. The results of analyzing the mean value of a change rate in the bone mineral densities of lumbar vertebrae (second to fourth lumbar vertebrae) at final are shown in the following Tables <NUM>-<NUM> and <NUM>-<NUM>. The numerical values in the tables show a mean value of a change rate (%) from the beginning.

It has been reported that the risks of the vertebral bone fractures would be <NUM> times by a decrease in the bone mineral densities of lumbar vertebrae by <NUM> SD (Non-Patent Publication <NUM>).

The increase in the bone mineral densities of lumbar vertebrae by the administration was analyzed using the bone mineral densities of lumbar vertebrae at the beginning or the number of prevalent vertebral bone fractures as an index. As a result, the increase in the bone mineral densities of lumbar vertebrae by the administration showed the tendency of being high along with the decrease in the bone mineral densities of lumbar vertebrae at the beginning, and conversely the increase in the bone mineral densities of lumbar vertebrae by the administration showed the tendency of being low along with the increase in the number of prevalent vertebral bone fractures.

The subjects to be analyzed for the efficacies were divided into subgroups in which the value of serum osteocalcin at the beginning was used as an index. The results of analyzing the time transitions of the mean value of a change rate in the bone mineral densities of lumbar vertebrae (second to fourth lumbar vertebrae) and in the femoral neck part are shown in the following Tables <NUM>-<NUM> and <NUM>-<NUM>. The numerical values in the tables show a mean value of a change rate (%) from the beginning.

The subjects to be analyzed for the efficacies were divided into subgroups in which the value of blood P1NP at the beginning was used as an index. The results of analyzing the time transitions of the mean value of a change rate in the bone mineral densities of lumbar vertebrae (second to fourth lumbar vertebrae) and the femoral neck part are shown in the following Tables <NUM>-<NUM> and <NUM>-<NUM>. The numerical values in the tables show a mean value of a change rate (%) from the beginning.

On the bases of the data of the above four tables, the calculated results that the mean value of a change rate in bone mineral densities at final (Test Drug Group) of the subgroup in which the OC or P1NP concentration at the beginning was the lowest was divided by the mean value of a change rate in bone mineral densities at final (Control Drug Group) of the subgroup in which the OC or P1NP concentration at the beginning was the lowest are shown the following Table <NUM>-<NUM>.

The treatment with a test drug was considered to be particularly excellent from the viewpoint of the effects of increasing the bone mineral density of femoral neck part when the patients having relatively low blood OC concentrations (for example, less than <NUM> (ng/mL)) were used as subjects.

The time transitions or the like of the incidence rate of new vertebral bone fractures and the incidence rate of worsening vertebral bone fractures in accordance with a Kaplan-Meier method in the subjects to be analyzed for the efficacies are shown in Tables <NUM>-<NUM> and <NUM>-<NUM>.

The time transitions or the like of the incidence rate of clinical vertebral bone fractures in accordance with a Kaplan-Meier method in the subjects to be analyzed for the efficacies are shown in the following Table <NUM>-<NUM>.

According to the above data for the incidence rate of vertebral bone fractures, it can be considered that the treatment with a test drug is excellent also from the viewpoint of inhibiting the vertebral bone fractures in general, as compared to the treatment with a control drug.

The time transitions of the bone resorption markers in the subjects to be analyzed for the efficacies are shown in the following Tables <NUM>-<NUM> to <NUM>-<NUM>.

The time transitions of the bone resorption markers accompanying the treatment with a test drug were of the same level or slightly inhibited, as compared to the time transitions of the bone resorption markers accompanying the treatment with a control drug (<FIG>).

Non-Patent Publication <NUM> has reported that the daily administration of a test drug enhances the bone resorption markers or the like. Further, in Non-Patent Publication <NUM> corroded surfaces indicating bone resorption are found in void surfaces in cortical bones caused by the daily administration of a test drug (see, <FIG> etc.), whereby suggesting that there is a deep relationship between the porosity of the cortical bones and the increase in bone resorption. In light of the contents or the like of these publications, it is assumed that the time transitions of the bone resorption markers in the treatment of twice a week in this case suggests that the treatment of administration of twice a week is a treatment that does not show an increase in bone turnover so as to increase a void ratio of cortical bone as compared to that of the treatment of administration of once a week.

The time transitions of the bone formation markers in the subjects to be analyzed for the efficacies are shown in the following Tables <NUM>-<NUM> and <NUM>-<NUM>.

The time transitions of the bone formation markers accompanying the treatment with a test drug were at high levels, as compared to the time transitions of the bone formation markers accompanying the treatment with a control drug (<FIG> and <FIG>). In particular, at an early stage after the beginning of administration (meaning herein until <NUM> weeks or so after the beginning of administration), the treatment of administration of twice a week had a significantly high change rate in the bone formation markers, as compared to the treatment of administration of once a week. In other words, it can be considered that an increase in bone formation is excellent, whereby it can be thought that the treatment of administration of twice a week possibly shows an even larger increase rate of bone mineral density, as compared to that of the treatment of administration of once a week.

The following aggregate analysis was performed by defining as test individuals subjects to be analyzed for safety who were administered with a test drug or a control drug in the treatment phase at least one or more times. The treatment-emergent adverse event (TEAE) means adverse events that emerged in the treatment phase.

The expression ratio for side effects by the administration of a test drug was markedly decreased, as compared to the expression ratio for side effects by the administration of a control drug.

The expression ratios for side effects were classified into three, the expression ratio for side effects of TEAE, the expression ratio for side effects of serious adverse events, and the expression ratio for side effects of other important adverse events to analyze. As a result, the expression ratio for side effects by the administration of a test drug was markedly decreased as compared to the expression ratio for side effects by the administration of a control drug in all of the expression ratios for side effects. The important adverse events as used herein were defined as adverse events that resulted in being serious or in discontinuation. In addition, the adverse events excluding "the serious adverse events" from "the important adverse events" were defined as "other important adverse events.

The expression ratios for adverse events and side effects relating to nausea, vomiting or the like having relatively high expression rations that are common in both the groups showed a low tendency in Test Drug Group, as compared to those of Control Drug Group. In addition, the expression ratios for adverse events and side effects of "headache" or "fervescence" showed a low tendency in Test Drug Group, as compared to those of Control Drug Group.

As a result of the aggregate analysis of the adverse events and the side effects for each organ, the expression ratios for adverse events and side effects showed a low tendency in Test Drug Group, as compared to those of Control Drug Group in all the disorders or conditions of the nervous system disorders, the gastrointestinal disorders, the general and systemic disorders and administration site conditions, the cardiac disorders, and the vascular disorders.

As mentioned above, it has been known that shocks, or unconsciousness accompanying a transient drastic blood pressure drop, convulsion, or fall is found from immediately after the administration over several hours of a daily administered preparation or a once-weekly administered preparation of PTH (Non-Patent Publications <NUM> and <NUM>).

Here, as to the events associated with blood pressure drop, the expression ratios for adverse events and side effects showed a low tendency in Test Drug Group as compared to those of Control Drug Group. Further, as to the events associated with shocks or unconsciousness, Test Drug Group showed excellent safety such that the expression of adverse events and side effects was not found at all.

In Test Drug Group, the dropping tendencies of the mean value of the change rates in systolic blood pressure (value after administration - value before administration) were the same for all of the test timings (after <NUM>, <NUM>, <NUM>, <NUM> and <NUM> weeks). On the other hand, in Control Drug Group, the same mean value particularly had a large dropping range after <NUM>, <NUM>, and <NUM> weeks, as compared to that of Test Drug Group. The extent of blood pressure drop was from -<NUM> to -<NUM> mmHg in Test Drug Group, and from - <NUM> to -<NUM> mmHg in Control Drug Group, so that the blood pressure drop in Test Drug Group were mild as compared to the blood pressure drop in Control Drug Group.

In Test Drug Group, the dropping tendencies of the mean value of the change rate in diastolic blood pressure (value after the administration - value before the administration) were the same for all of the test timings (after <NUM>, <NUM>, <NUM>, <NUM> and <NUM> weeks). On the other hand, in Control Drug Group, the same mean value particularly had a large dropping range after <NUM>, <NUM>, and <NUM> weeks. The extent of blood pressure drop was from -<NUM> to -<NUM> mmHg in Test Drug Group, and from -<NUM> to -<NUM> mmHg in Control Drug Group, so that the blood pressure drop in Test Drug Group were mild as compared to the blood pressure drop in Control Drug Group.

The tendencies of decreasing the expression ratios in the frequency of side effects by aging were even more strongly observed in Test Drug Group, and in particular, the expression ratios of the frequency of side effects were markedly lowered in the patients of Test Drug Group of age <NUM> or older.

Test Drug Group showed excellent safety regardless of the genders, as compared to those of Control Drug Group, and in particular male individuals had remarkably decreased expression ratios for side effects.

The treatment continuality showed high tendencies in Test Drug Group as compared to those of Control Drug Group.

The proportion of discontinuation of the treatment due to adverse events was low in Test Drug Group as compared to that of Control Drug Group. In addition, the discontinuation due to adverse events at less than <NUM> weeks was <NUM> individuals in Test Drug Group, in contrast to <NUM> individuals in Control Drug Group, so that in Test Drug Group, the discontinuation cases due to adverse events at an early stage of the treatment was particularly fewer.

The treatment with Test Drug Group was found to have improvements in the treatment continuality by decreasing the expression ratios of adverse events or side effects such as nausea and vomiting, as compared to the treatment with Control Drug Group.

Using <NUM> test individuals who completed the treatment over <NUM> weeks out of Test Drug Group (hereinafter referred to as Test Drug Group with Treatment Completed) as subjects, the proportion occupying the weeks in which the intervals of administration in a week (not including the days of administration) out of <NUM> weeks, the number of weeks of the entire period of administration, were <NUM>-day and <NUM>-day intervals (%) (hereinafter referred to as the proportion in compliance with administration of <NUM>-day to <NUM>-day intervals) was calculated for each test individual. At this time, it was considered that the weeks that satisfy the following conditions (<NUM>) or (<NUM>) did not fall under the weeks in which the intervals of administration in a week (not including the days of administration) were <NUM>-day and <NUM>-day intervals.

(<NUM>) Weeks in a case where the period of the course from the day on which a control drug placebo was administered to the day on which a next control drug placebo was administered was within <NUM> days.

(<NUM>) Weeks in a case where a test drug was administered without intervals of administration, or administered with a <NUM>-day administration interval, a <NUM>-day administration interval, and a <NUM>-day administration interval, when the period of the course from the day on which a control drug placebo was administered to the day on which a next control drug placebo was administered was <NUM> or more days.

Having defined the proportion in compliance with administration of <NUM>-day to <NUM>-day intervals as described above, the following five aggregate analyses were carried out.

Here, the assessment items for the efficacies were change rates in bone mineral densities of lumbar vertebrae (second to fourth lumbar vertebrae), change rates in bone mineral densities of femoral neck part, change rates in bone mineral densities of femoral proximal total, clinical fracture incidence rates, and non-vertebral fracture incidence rates. In addition, the assessment items for the safety were the expression ratios of all the side effects and the expression ratios of nausea (side effects).

Further, the mean of the number of administrations and the mean of the number of the administration period in each group to be compared were calculated.

Using <NUM> individuals of Test Drug Group with Treatment Completed as subjects, the mean of the number of administrations and the mean of the administration period were calculated for each of the proportions in compliance with administration intervals. The results are shown in the following Table <NUM>-<NUM>.

In the comparisons of both cases when distinguished by <NUM>% or more and that of less than <NUM>% of the proportion in compliance with administration of <NUM>-day to <NUM>-day intervals, there were no significance differences in the mean of the number of administrations and the mean of the administration period, and were of the same levels. In the cases of comparing a specified value or more and less than a specified value for each of the values for the proportion in compliance with administration of <NUM>-day to <NUM>-day intervals of <NUM>%, <NUM>%, <NUM>% and <NUM>%, similar results were also obtained as the case where a proportion in compliance with administration of <NUM>-day to <NUM>-day intervals of <NUM>% or more. Therefore, it was considered that there were no differences in the mean of the number of administrations and the mean of the administration period even in different proportions in compliance with administration of <NUM>-day to <NUM>-day intervals, so that there are no differences in the exposed amount of the investigational product.

The mean value of change rates (%) when distinguished by a specified value or more / less than a specified value in bone mineral densities for the lumbar vertebrae, the femoral neck part, and the femoral proximal total was calculated of the proportions in compliance with administration of <NUM>-day to <NUM>-day intervals. The results are shown in the following Tables <NUM>-<NUM> to <NUM>-<NUM>.

In addition, graphs showing the transitions of the mean value of change rates (%) in each of the bone mineral densities of lumbar vertebrae (second to fourth lumbar vertebrae), the bone mineral densities of the femoral neck part, and the bone mineral densities of the femoral proximal total by comparing the values of a specified value or more / less than a specified value for each of the proportions in compliance with the administration of <NUM>-day to <NUM>-day intervals are shown in <FIG>.

As mentioned above, the bone mineral densities of lumbar vertebrae (second to fourth lumbar vertebrae) are a main assessment item for the efficacies of the present test. In view of the above, the analysis results on the influences given by fluctuations of a specified value to the mean value of change rates (%) in bone mineral densities of lumbar vertebrae (second to fourth lumbar vertebrae) indicated by patients having a proportion in compliance with the administration of <NUM>-day to <NUM>-day intervals of a specified value (%) or more at the time point of <NUM> weeks after the beginning of administration are shown in <FIG>.

In the layer where the proportion in compliance with the administration of <NUM>-day to <NUM>-day intervals is a specified value or more, the larger the proportion in compliance with the administration of <NUM>-day to <NUM>-day intervals, the mean value of change rates (%) in bone mineral densities tended to be higher. Therefore, it was considered that the higher the proportion occupied by the weeks in which the intervals of administration in a week (not including the days of administration) was <NUM>-day and <NUM>-day intervals, the higher the therapeutic effects obtained. More specifically, excellent therapeutic effects are exhibited in an embodiment where the same proportion is <NUM>% or more, and even more remarkable therapeutic effects can be acquired in an embodiment where the same proportion is <NUM>% or more. Moreover, in taking strong positive correlative tendencies of the same proportion and the therapeutic effects into account, it was considered that the therapeutic effects would be generally maximized when the same proportion is <NUM>%.

On the other hand, there were two cases where the compliance rate of the administration of <NUM>-day to <NUM>-day intervals (<NUM>-day to <NUM>-day intervals including the days of administration) was <NUM>%, and the administration was carried out at the frequency of twice a week by generally <NUM>-day and <NUM>-day intervals (<NUM>-day and <NUM>-day intervals including the days of administration). The mean of change rates (%) in the bone mineral densities of lumbar vertebrae (second to fourth lumbar vertebrae) for these two cases were analyzed. As a result, at <NUM> weeks after the beginning of the administration, the mean value for one case was <NUM>%, and that for the other case was <NUM>%. The inventor considers that the results also suggest that it is useful to comply with the administration of <NUM>-day to <NUM>-day intervals (<NUM>-day to <NUM>-day intervals including the days of administration) when the administration was carried out twice a week.

The incidence rates of clinical bone fractures and non-vertebral bone fractures when distinguished by a specified value or more and less than a specified value of each of the proportions in compliance with the administration of <NUM>-day to <NUM>-day administration were calculated. The results are shown in the following Tables <NUM>-<NUM> to <NUM>-<NUM>.

As mentioned above, the clinical bone fractures are bone fractures that embrace vertebral and non-vertebral bone fractures. In view of the above, the analysis results on the influences given by fluctuations of a specified value to the bone fracture incidence rate (%) for the clinical bone fractures indicated by patients having a proportion in compliance with the administration of <NUM>-day to <NUM>-day intervals of a specified value (%) or more are shown in <FIG>.

In the layer where the proportion is a specified value or more, the larger the proportion in compliance with the administration of <NUM>-day to <NUM>-day intervals, the bone fracture incidence rate (%) tended to be generally decreasing. Therefore, it was considered that the higher the proportion occupied by the weeks in which the intervals of administration in a week (not including the days of administration) is <NUM>-day and <NUM>-day intervals, the higher the therapeutic effects obtained. More specifically, excellent therapeutic effects are exhibited in an embodiment where the same proportion is <NUM>% or more, and even more remarkable therapeutic effects can be acquired in an embodiment where the same proportion is <NUM>% or more. Moreover, in taking strong positive correlative tendencies of the same proportion and the therapeutic effects into account, it was considered that the therapeutic effects would be generally maximized when the same proportion is <NUM>%.

The time transitions of the bone metabolism markers (urine NTX (u-NTX), serum NTX (s-NTX), CTX, OC, and PINP) when distinguished by a specified value or more / less than a specified value of each of the proportions in compliance with administration intervals were calculated. The results are shown in the following Tables <NUM>-<NUM> to <NUM>-<NUM>.

As a bone metabolism marker for observing bone formation action of a daily administered preparation or a once-weekly administered preparation, each containing teriparatide or a salt thereof as an active ingredient, serum osteocalcin (OC) has been widely used (Non-Patent Publication <NUM> or the like). In addition, in the administration with a test drug in the present disclosure, the peak of OC elevation is found roughly four weeks after the beginning of administration (<FIG>). In view of the above, the analysis results on the influences given by fluctuations of a specified value to OC indicated by patients having a proportion in compliance with the administration of <NUM>-day to <NUM>-day intervals of a specified value (%) or more at four weeks after the beginning of administration are shown in <FIG>.

As to a bone formation marker OC, contrary to the therapeutic effects mentioned above, a distinct correlation with the proportion in compliance with the administration of <NUM>-day to <NUM>-day intervals was not found in the layer in which the proportion was at a level of a specified value or more.

It has been known that a parathyroid hormone drug is a bone formation accelerator (Non-Patent Publication <NUM>), and the dissociation of a bone formation marker and a bone resorption marker is recognized as an efficacy index in the daily osteoporosis treatment using teriparatide (Non-Patent Publication <NUM>). Therefore, with regard to the correlation with the proportion in compliance with the administration of <NUM>-day or <NUM>-day intervals, the present analysis results in which different tendencies were shown between the therapeutic effects and the bone formation marker OC were considered to be highly epoch-making in light of the findings of the conventional teriparatide therapies.

As mentioned in the above <NUM>. <NUM>, the nausea was a side effect having the highest expression ratio. In view of the above, the analysis results on the influences given by fluctuations of a specified value (%) to the expression ratio (%) of nausea indicated by patients having a proportion in compliance with the administration of <NUM>-day to <NUM>-day intervals of a specified value (%) or more are shown in <FIG>.

In the group in which the proportion in compliance with the administration intervals is a specified value or more, the larger the proportion in compliance with the administration intervals, the expression ratio of nausea (side effects) tended to be low. Therefore, it was considered that the higher the proportion occupied by the weeks in which the administration intervals in a week (not including the days of administration) are <NUM>-day and <NUM>-day intervals, the therapy has higher safety. More specifically, excellent safety was shown in an embodiment in which the same proportion was <NUM>% or more, and taking the strong positive correlative tendencies between the same proportion and safety into account, it was considered that the safety is generally probably maximized when the same proportion is <NUM>%.

To evaluate the influences of the administration frequencies of teriparatide on the bone metabolism and the bone tissue morphology, six-month old female rabbits were subcutaneously administered with an agent in a manner that a weekly dosage of teriparatide was adjusted to <NUM>µg/kg at a frequency of once a week, twice a week or seven times a week over <NUM> weeks, or with a control drug without containing teriparatide at a frequency of seven times a week over <NUM> weeks (Table <NUM>-<NUM>). Also, the bone mineral density and the bone strength of the tibiae were measured. The teriparatide solution which was administered was appropriately prepared by dissolving teriparatide acetate in a water for injection, filtering the solution, filling the filtrate in a vial, freeze-drying to give a preparation, and dissolving the preparation in a physiological saline upon use.

The bone mineral densities of the tibiae were analyzed in divided regions. As a result, the administration of teriparatide remarkably increased the bone mineral densities in the proximal part (<NUM>/<NUM> site) rich in trabecular bones, as compared to those of the control group, and the bone mineral densities of the group administered twice a week had a higher value than that of the group administered once a week in this site. The present test results agree with the test results for Working Example <NUM> (Table <NUM>-<NUM>) showing that the bone mineral densities of the group administered twice a week had a higher value than that of the group administered once a week in the lumbar vertebrae (second to fourth lumbar vertebrae) rich in trabecular bones in the same manner as the proximal part of the tibiae (the lumbar vertebrae being composed of <NUM>% trabecular bones, and the centrum being composed of <NUM>% trabecular bones; Non-Patent Publication <NUM>).

Three-point bending strength of the tibiae collected after the end of the administration period was measured. As a result, the maximum load showed higher values in the group administered with the present drug twice a week and the group administered seven times a week, than the control group.

In the group administered seven times a week, the formation of trabecular bones on the endocortical surfaces, a large number of intracortical voids (increase of cortical porosity), and disorderedness in a lamellar structure were observed, but none of these findings were observed in the group administered once a week and the group administered twice a week.

Non-Patent Publication <NUM> has reported that the administration of teriparatide at high frequencies enhances the bone turnover, suggesting that the increase in void ratios of the cortical bone with teriparatide is strongly influenced by the administration frequencies. In the present working example, the enhancement in the bone turnover that would increase the void ratio of the cortical bones was not found, in the therapy of administration of twice a week, despite the doubling in the administration frequencies of the therapy of administration of once a week. This matter, in light of Non-Patent Publication <NUM>, was considered to be unexpected and epoch-making results.

In addition, Non-Patent Publication <NUM> has reported that the daily administration of teriparatide increases a bone resorption marker. Further, it is suggested that in Non-Patent Publication <NUM>, an eroded surface showing bone resorption in a void surface of the cortical bone caused by daily administration of teriparatide has been found (see, Fig. <NUM> c or the like), so that the porosity of the cortical bone has a deep relationship with the enhancement of bone resorption.

Claim 1:
Teriparatide or a salt thereof for use in preventing or treating
osteoporosis in a human patient, characterized in that the teriparatide or a salt thereof is administered in a unit dose of <NUM>µg at a frequency of twice a week,
wherein the intervals, not including the days of administration, of administration of twice a week are a <NUM>-day interval and a <NUM>-day interval.