WO2011030774A1 - 1回当たり100~200単位のpthが週1回投与されることを特徴とする、pth含有骨粗鬆症治療/予防剤 - Google Patents
1回当たり100~200単位のpthが週1回投与されることを特徴とする、pth含有骨粗鬆症治療/予防剤 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone (parathormone); Parathyroid hormone-related peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
- A61K33/10—Carbonates; Bicarbonates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the present invention relates to a therapeutic or prophylactic agent for osteoporosis containing PTH as an active ingredient.
- the present invention also relates to a fracture inhibiting or preventing agent containing PTH as an active ingredient.
- the present invention relates to said medicament, characterized in that 100 to 200 units of PTH are administered once a week.
- Osteoporosis is a “disease characterized by decreased bone strength and an increased risk of fractures”.
- PTH parthyroid hormone
- PTH is a hormone involved in the regulation of blood calcium concentration.
- PTH is also known to have an action of promoting calcium absorption in the intestinal tract by increasing the production of active vitamin D 3 in the kidney in vivo (Non-patent Document 1).
- Patent Document 1 discloses that the osteoporotic patient's bone of the sea surface bone by subcutaneously administering 100 or 200 units of PTH per administration over a 26-week administration period at a frequency of once a week. Disclosed is a method of treating osteoporosis that increases density and does not decrease cortical bone density.
- Patent Document 1 discloses that these treatment methods simply induce an increase in bone density, while the treatment method can increase the bone strength of a patient with osteoporosis or reduce the risk of fracture. It is not specified whether or not. Moreover, only PTH was used alone and no calcium agent was used in combination.
- Non-patent document 1 shows that in a clinical trial related to treatment of osteoporosis by PTH, hypercalcemia was observed in 11% of the patients when blood was collected 4 to 6 hours after administration of PTH (20 ⁇ g / day) to the patients. Discloses that 3% of hypercalcemia was observed. Furthermore, Non-Patent Document 1 shows that although serum calcium returned to normal in almost all patients before the next PTH administration, a sustained increase in serum calcium was observed in one of 541 patients. It also discloses that treatment has been discontinued.
- Non-patent document 2 discloses that serum calcium after administration of this drug is clinically unaffected for daily subcutaneous administration of PTH in combination with a calcium agent, but serum calcium after administration has also increased. ing.
- Non-Patent Document 3 is a package insert of the daily subcutaneous preparation disclosed in Non-Patent Document 2. This document reports that in clinical trials, transient hypercalcemia after administration of the formulation was observed in disclosing various adverse events after administration of the formulation. Furthermore, Non-Patent Document 3 discloses that a side effect report of hypercalcemia was reported in the post-marketing surveillance of the preparation.
- Non-Patent Documents 1 to 3 disclose examples of side effects of hypercalcemia in the treatment of osteoporosis of PTH, and it can be said that the disclosed treatment methods are not sufficient from the viewpoint of safety.
- JP-A-8-73376 WO00 / 10596 JP 5-306235 JP-A 64-16799 WO02 / 002136 JP 2003-095974 A
- An object of the present invention is to provide a method for treating or preventing osteoporosis by PTH which is highly safe and has excellent efficacy and effect. Furthermore, the subject of this invention is providing the fracture suppression thru
- the present inventors have conducted extensive research and development, and as a result, surprisingly, by limiting the dose / interval of PTH, it was excellent in both efficacy, effect and safety. It has been found that this is a treatment or prevention method for osteoporosis. Further, it has been found that by specifying the dose and the administration interval of PTH, it becomes a highly safe fracture suppression / prevention method. Furthermore, it has also been found that these methods are particularly effective for high-risk patients.
- the present invention relates to the following.
- An osteoporosis treatment or prevention agent containing PTH as an active ingredient, which is used in combination with a calcium agent and 100 to 200 units of PTH is administered once a week.
- the osteoporosis treatment or prevention agent according to [1] or [2] above, wherein the calcium agent used in combination is administered in an amount of 200 to 800 mg per day as calcium.
- the osteoporosis treatment or prevention agent according to any one of [1] to [4] above which is administered over a period exceeding 24 weeks or 48 weeks.
- a combination or medical kit comprising the osteoporosis treatment or prevention agent according to any one of [1] to [12] and at least one agent of the following (1) to (6).
- An osteoporosis treatment or prevention agent containing PTH as an active ingredient wherein 100 to 200 units of PTH are administered once a week, and secondary osteoporosis caused by a steroid, Alternatively, an osteoporosis treatment or prevention agent for treating or preventing diabetic osteoporosis.
- An osteoporosis treatment or prevention agent containing PTH as an active ingredient wherein 100 to 200 units of PTH are administered once a week, and having mild renal disorder or moderate renal disorder An osteoporosis treatment or prevention agent for administration to an osteoporosis patient.
- a fracture-suppressing or preventing agent containing PTH as an active ingredient, which is used in combination with a calcium agent and 100 to 200 units of PTH is administered once a week.
- the fracture-suppressing or preventing agent according to [18] or [19] above, wherein the calcium agent used in combination is administered as calcium in an amount of 200 to 800 mg per day.
- the osteoporosis therapeutic agent of the present invention is high in safety and excellent in efficacy and effect. Moreover, the fracture inhibiting or preventing agent of the present invention is highly safe and useful.
- FIG. 1 is a graph showing the results of changes in serum calcium concentration by administration group (high risk person, low risk person).
- the influence of the test drug administration on the time-dependent change in the incidence of new vertebral fractures is shown.
- the test drug administration group was designated as “PTH200 group”, and the control drug administration group as “P group”.
- the influence of the test drug administration on the time-dependent change in the incidence of new vertebral fractures is shown.
- the test drug administration group was designated as “PTH200 group”, and the control drug administration group as “P group”.
- the test result (“PTH200 group”) or a control drug (“P group”) is shown about the result tested about the fluctuation
- the ratio of urinary calcium value / urine creatine value was compared between before administration and the observation week.
- the measurement of urinary calcium was carried out at the beginning, after 12, 24, 48 and 72 weeks.
- a standard concomitant drug (calcium 610 mg, vitamin D 3 400 IU, and magnesium 30 mg) was taken after dinner once a day from the time of obtaining consent until the end of the trial.
- the test result (“PTH200 group") or a control drug ("P group”) is shown about the result tested about the fluctuation
- Serum calcium was measured at the start, after 12, 24, 48, and 72 weeks.
- a standard concomitant drug (calcium 610 mg, vitamin D 3 400 IU, and magnesium 30 mg) was taken after dinner once a day from the time of obtaining consent until the end of the trial.
- the present invention 100 to 200 units of PTH per administration is administered once a week (hereinafter referred to as “once a week” may be referred to as “biweekly”).
- a preventive method or a method for suppressing or preventing fractures is provided.
- the present invention also provides an osteoporosis treatment / prevention agent or fracture suppression / prevention agent comprising PTH as an active ingredient, wherein 100 to 200 units of PTH are administered every other week.
- the present invention provides use of PTH for the production of the osteoporosis treatment or prevention agent or the fracture suppression or prevention agent.
- PTH Active Ingredient PTH as an active ingredient of the present invention
- human PTH (1-84) which is a human parathyroid hormone
- human PTH (1-84) Peptides having a molecular weight of about 4,000 to 10,000 having equivalent or similar activity are included.
- PTH includes both natural PTH, PTH produced by genetic engineering techniques, and PTH synthesized by chemical synthesis.
- PTH can be produced by a genetic engineering technique known per se (Non-patent Document 8).
- PTH can be synthesized by a peptide synthesis method known per se (Non-patent Document 11), for example, a solid phase method in which a peptide chain is extended from the C-terminus on an insoluble polymer carrier (solid phase). method) (Non-patent Document 4).
- the origin of PTH of this invention is not restricted to a human, A rat, a cow, a pig, etc. may be sufficient.
- human PTH means a peptide represented by a partial amino acid sequence consisting of amino acid sequence n-th to m-th of human PTH (1-84).
- human PTH (1-34) means a peptide represented by a partial amino acid sequence consisting of the first to 34th amino acid sequences of human PTH (1-84).
- the PTH that is the active ingredient of the present invention may be a salt formed with one or more volatile organic acids.
- the volatile organic acid include trifluoroacetic acid, formic acid, acetic acid and the like, and preferably acetic acid.
- the ratio of the free PTH and the volatile organic acid when forming a salt is not particularly limited as long as the salt is formed.
- human PTH (1-34) has 9 basic amino acid residues and 4 acidic amino acid residues in its molecule. Five amino acid residues can be the chemical equivalent of acetic acid.
- acetic acid content expressed as acetic acid weight ⁇ 100 (%) / peptide weight of human PTH (1-34) is used as the amount of acetic acid
- one theory is that human PTH (1-34) which is free form
- the chemical equivalent of acetic acid is about 7.3% (% by weight).
- free human PTH (1-34) is sometimes referred to as teriparatide
- teriparatide acetate is sometimes referred to as teriparatide acetate.
- the acetic acid content in teriparatide acetate is not particularly limited as long as teriparatide and acetic acid form a salt, and may be, for example, the theoretical chemical equivalent of 7.3% or more, or 0 to 1%. . More specifically, the acetic acid content in teriparatide acetate may be 1 to 7%, preferably 2 to 6%.
- human PTH As PTH, human PTH (1-84), human PTH (1-34), human PTH (1-38), hPTH (Non-patent Document 5), human PTH (1-34) NH 2 , [Nle 8, 18 ] Human PTH (1-34), [Nle 8,18 , Tyr 34 ] Human PTH (1-34), [Nle 8,18 ] Human PTH (1-34) NH 2 , [Nle 8,18 , Tyr 34 ] Human PTH (1-34) NH 2 , rat PTH (1-84), rat PTH (1-34), bovine PTH (1-84), bovine PTH (1-34), bovine PTH (1-34) NH 2 and the like are exemplified.
- preferable PTH examples include human PTH (1-84), human PTH (1-38), human PTH (1-34), and human PTH (1-34) NH 2 (Patent Document 3, etc.).
- Particularly preferred PTH includes human PTH (1-34). More preferred PTH is human PTH (1-34) obtained by chemical synthesis, and the most preferred PTH is teriparatide acetate (Example 1).
- the osteoporosis therapeutic agent or fracture inhibiting / preventing agent according to the present invention is characterized by being used in combination with other drugs.
- the combined use with other drugs means that an osteoporosis therapeutic agent or fracture inhibiting / preventing agent according to the present invention and a certain drug (other drug) different from this drug are used in combination.
- Calcium can be preferably exemplified as another drug of the present invention.
- the combined use with other drugs does not exclude further combinations with other drugs other than the other drugs. Therefore, as a combination with calcium, for example, Combined with calcium only, Combination with calcium and vitamin D (including derivatives thereof) and / or magnesium alone, Is also preferable. Therefore, calcium agents can be exemplified as specific modes of other drugs, (1) a calcium preparation containing calcium as a medicinal ingredient, (2) Calcium agents each containing calcium, vitamin D (including derivatives thereof) and magnesium as medicinal ingredients can be preferably exemplified.
- the form (administration frequency, administration route, administration site, dosage, etc.) of the osteoporosis therapeutic agent or fracture inhibiting / preventing agent according to the present invention and other agents in combination is not particularly limited, and is a doctor corresponding to the patient. It can be determined appropriately depending on the prescription of
- the calcium agent when a calcium agent is used in combination as the other drug, the calcium agent may be administered simultaneously with the osteoporosis therapeutic agent or fracture inhibiting / preventing agent according to the present invention containing PTH as an active ingredient (ie, weekly 1). Once) or more frequently, and may be administered once to several times a day. Therefore, the other drug may be a combination of the osteoporosis treatment / prevention agent or the fracture suppression / prevention agent according to the present invention, and the osteoporosis treatment / prevention or fracture suppression / prevention agent according to the present invention.
- the preparation may be separate from other drugs.
- An example of such a calcium agent is “New Calcium (trademark) D 3 ” (distributor: Daiichi Sankyo Healthcare, manufacturer / seller: Nitto Pharmaceutical Co., Ltd.).
- other drugs may be administered by the same or different routes of administration together or sequentially (ie, at different times) with the osteoporosis treatment / prevention agent or fracture suppression / prevention agent according to the invention.
- the dosage form of other drugs is not particularly limited, and examples thereof include tablets, capsules, and fine granules.
- the other drug is a calcium agent
- the calcium agent preferably contains 100 to 400 (preferably 150 to 350) mg of calcium per unit dosage form as calcium.
- 200 to 800 mg of calcium will be administered per day.
- the above other agents include calcium carbonate, such as precipitated calcium carbonate, calcium lactate, calcium carbonate, calcium chloride, calcium gluconate, calcium aspartate, calcium phosphate, calcium hydrogen phosphate, calcium citrate.
- known drugs containing such as active ingredients can be exemplified.
- Agents containing precipitated calcium carbonate are preferred.
- medical agent may contain the excipient
- Patent Document 6 It is known that gastrointestinal symptoms such as vomiting, nausea, nausea, stomach upset, stomach discomfort, and heartburn are transiently observed in a certain proportion of PTH-administered patients.
- the present inventors tested the timing and effectiveness of various antiemetics for transient nausea and vomiting associated with test drug administration.
- purinperan (generic name of its medicinal component is metoclopramide), nauselin (its The generic name of the medicinal ingredient is domperidone), Gaster D (generic name of the medicinal ingredient is famotidine), gasmotin (generic name of the medicinal ingredient is mosapride citrate), Takepron OD (generic name of the medicinal ingredient is lansoprazole) and It was confirmed that Rokujin Maru was effective against nausea or vomiting associated with PTH administration (Example 2).
- these antidepressants are preferred as further other drugs, nauselin (generic name of its medicinal ingredient is domperidone), gasmotin (generic name of its medicinal ingredient is mosapride citrate) and / or Rokujinmaru, Can be mentioned.
- the dosage of these antiemetics can be appropriately set by a doctor or the like according to the patient's symptoms.
- examples of the administration period include 24 weeks or more, 26 weeks or more, 48 weeks or more, 52 weeks or more, 72 weeks or more, or 78 weeks or more, and most preferably 78 weeks or more.
- hypercalcemia was not confirmed as an adverse event (Example 1).
- the dosage is 100 to 200 units per dose.
- 1 unit amount of PTH can be measured by an activity measurement method known per se (Non-patent Document 9).
- the dosage is preferably 100 or 200 units per dose, most preferably 200 units per dose.
- V administration interval As a result of conducting a double-blind comparative clinical trial in which PTH is administered at a frequency of once a week, the present inventors have found that the significant fracture-suppressing effect by the administration and the early stage of 24 or 26 weeks later. Onset of the effect was observed, while hypercalcemia as an adverse event was not confirmed (Examples 1 and 2). Accordingly, one feature of the present invention is that the administration interval is every other week.
- the osteoporosis treatment / prevention agent / fracture suppression / prevention agent of the present invention can be administered by an appropriate administration route according to the preparation form.
- the osteoporosis treatment or prevention agent or fracture prevention or prevention agent of the present invention when it is an injection, it can be administered intravenously, artery, subcutaneously, intramuscularly, or the like.
- the inventors of the present invention have demonstrated that as a result of subcutaneous injection of PTH, excellent efficacy / effect and safety are shown (Examples 1 and 2). Therefore, the present invention can preferably illustrate a subcutaneous administration route as its administration route.
- Osteoporosis according to the present invention is not particularly limited, and includes both primary osteoporosis and secondary osteoporosis.
- Examples of primary osteoporosis include regressive osteoporosis (postmenopausal osteoporosis and senile osteoporosis) and idiopathic osteoporosis (post-pregnancy osteoporosis, juvenile osteoporosis, etc.).
- Secondary osteoporosis is osteoporosis induced by a specific disease or cause of a specific drug, such as a specific drug, rheumatoid arthritis, diabetes, hyperthyroidism, sexual dysfunction, immobility, nutrition, etc.
- a congenital disease can be cited as the cause.
- Examples of the specific drug include steroids.
- Preferred examples of osteoporosis according to the present invention include osteoporosis with a high risk of fracture.
- the indication of the present invention to osteoporosis with a high risk of fracture means the indication of the present invention to the following high-risk patients.
- primary osteoporosis can be preferably exemplified as osteoporosis according to the present invention, and regression osteoporosis can be most preferably exemplified.
- a primary osteoporosis patient according to the present invention a primary osteoporosis patient taking a steroid that induces secondary osteoporosis can be preferably exemplified.
- an osteoporosis patient according to the present invention an osteoporosis patient having at least one complication of diabetes, hypertension and hyperlipidemia can be preferably exemplified, and a combination of at least any one of diabetes, hypertension and hyperlipidemia can be exemplified. More preferably, patients with primary osteoporosis having the disease can be exemplified.
- Non-patent Document 16 It is known that diabetes is likely to be a risk factor for osteoporotic fractures.
- Non-patent Document 22 As a result of administering PTH to sreptozotocin-treated rats over 8 weeks, it has been reported that recovery of sea surface bone mass and turnover was observed (Non-patent Document 22). 3) In experiments on cultured cells, it has been reported that when exposed to high concentrations of glucose, the response to hPTH (1-34) falls (the effectiveness of PTH deteriorates) (Non-patent Document 20).
- the inventor has many views such as doctors who expect the effects of PTH administration to diabetic osteoporotic human patients (eg: http://www.richbone.com/kotsusoshosho/basic_shindan/tonyo.htm) However, I could't find a paper that proved the effect.
- the osteoporosis therapeutic agent / fracture inhibitor / preventive agent of the present invention reduces the risk of vertebral fractures for patients with complications of primary osteoporosis and diabetes. It is.
- the fracture according to the present invention is not particularly limited, and includes both vertebral fractures and non-vertebral fractures (Example 1), and includes pathological fractures caused by osteoporosis, osteogenesis imperfecta, bone tumors, traffic accidents, Includes traumatic fractures caused by bruises.
- it can be applied to fractures caused by osteoporosis, more preferably vertebral fractures caused by osteoporosis.
- the fracture site is not particularly limited, but typically, spinal compression fractures, femoral neck fractures, intertrochanteric fractures, femoral shaft fractures, humeral neck fractures, and distal radius fractures
- spinal compression fractures may be exemplified.
- the number of fractures according to the present invention is not particularly limited, and includes both single fractures and multiple fractures.
- a single fracture means a medical condition in which a bone breaks or cracks only once
- a multiple fracture means a medical condition in which two or more bones break or cracks.
- the number of fractures in multiple fractures is not particularly limited, but is preferably applied to 2 to 4 fractures.
- the vertebral fracture according to the present invention includes both new fractures and exacerbated fractures.
- the degree of deformation of the entire vertebral body can be classified as Grade, Grade0 (normal), Grade1 (vertebral body height reduced by about 20-25%, and vertebral body area reduced by 10-20%) , Grade2 (vertebral body height decreased by about 25-40% and vertebral body area decreased by 20-40%), Grade3 (vertebral body height decreased by approximately 40% or more, and vertebral body area decreased by 40% or more) It is common.
- the classification of new / exacerbation can be carried out according to the increase pattern of Grade according to the Genant's criterion.
- the present inventors have confirmed the exacerbation fracture-suppressing effect of the present invention in a clinical trial for patients with existing fractures (Example 2). Therefore, in the present invention, application to a patient having an existing fracture, more preferably an existing fracture, and a patient having the possibility of an exacerbated fracture can be exemplified as an osteoporosis patient.
- the bone strength reflects not only the bone density but also the bone quality, which means that not only the bone density but also bone quality factors such as bone microstructure and calcification define the bone strength (Non-patent Document 17).
- the present inventor believes that bone quality may affect not only bone strength but also the risk of developing diseases different from osteoporosis and the healing outcome of complications thereof. It was suggested that the osteoporosis treatment / prevention agent / fracture suppression / prevention agent of the present invention may be superior in these respects compared to the conventional treatment agent (Patent Document 2).
- rhPTH (1-34) was administered to osteoporotic patients, and as a result, not only bone mineral content (BMC) and bone mineral density (BMD) but also bone areas such as lumbar spine and femur were increased. Is disclosed. An increase in bone area means that the bone thickens outward.
- cortical bone thickness increased not inside the bone but inside the bone. That is, almost no change was observed in the thickness of the entire bone. This mechanism is considered to show the important clinical significance shown below, for example.
- the femur which is one of the long bones (the long bones that make up the limbs), comes into contact with the articular cartilage and other synovium and meniscus. Together with the knee joint.
- the contact surface is called a joint surface covered with cartilage having a thickness of about several millimeters. Examples of diseases that cause knee joint pain include knee osteoarthritis.
- this forteo administration is a conventional treatment method substantially equivalent to the PTH administration described in Patent Document 2, and as described above, this conventional method is a treatment method for thickening outside the bone.
- Thickening outward of the femur means an increase in the area of the joint surface, and the number of chondrocytes does not increase compared to the thickening of the bone. May promote joint destruction through damage to chondrocytes caused or exacerbated by an increase in.
- thickening inside the femur as in the present invention does not increase the joint surface, stabilizes the cartilage, and as a result, may not substantially promote joint destruction without increasing the burden on the cartilage.
- the inventor believes that there is. This suggests the possibility that osteoporosis treatment with this drug is a treatment that is gentler to the joint than the conventional osteoporosis treatment.
- Patent Document 2 when PTH is administered daily and thickened outside the bone, there is a possibility that a sufficient inhibitory effect on the enlargement of the end hole is not observed.
- an increase in the contact area between the vertebral body and the intervertebral disc reduces the distance between the vertebral bodies, leading to instability of the vertebral body, resulting in an increased risk of developing or exacerbating osteoarthritis. .
- the osteoporosis therapeutic agent / fracture inhibitor / preventive agent administration of the present invention increases the cortical bone thickness not to the outside of the bone but to the inside of the bone. May be sufficiently suppressed.
- Hip osteoarthritis is a acetabulum and thigh that form the hip joint because of poor blood flow to the joint or extreme weighting or overuse.
- the articular cartilage on the contact surface of the head of the bone has undergone wear, degeneration, and irreversible changes.
- the femoral cortical bone area of patients with hip osteoarthritis is significantly larger than that of healthy individuals (Non-patent Document 18).
- An increase in femoral cortical bone area means enlargement of the femur to the outside, and this may therefore be involved in the development or exacerbation of osteoarthritis.
- osteoporosis having at least one of the following diseases as a complication: joint pain, osteopathy spondylosis, osteoarthritis, hip osteoarthritis, and osteoarthritis of the jaw
- a patient preferably a patient with primary osteoporosis
- the present inventors evaluated the influence of the history of other osteoporosis medications on the efficacy of this drug within one year. As a result, it was revealed that primary osteoporosis patients with a history of taking other osteoporosis therapeutic agents have higher test drug effectiveness than patients with no history of medication (Example 2). Therefore, in the present invention, as an osteoporosis patient, an application to an osteoporosis patient who has a history of taking other osteoporosis therapeutic agents can be preferably exemplified, and an application to a patient with primary osteoporosis who has a history of taking other osteoporosis therapeutic agents can be further illustrated. Preferred examples can be given.
- osteoporosis therapeutic agents examples include L-calcium aspartate, alphacalcidol, raloxifene hydrochloride, elcatonin, menatetrenone, calcium lactate, and preferably, calcium L-aspartate, alphacalcidol, and elcatonin.
- the Other osteoporosis therapeutic agents may be used alone or in combination.
- osteoporosis therapeutic agent / fracture inhibitor / preventive agent of the present invention for 24 to 72 weeks or more to osteoporotic patients who have been administered other osteoporosis therapeutic agents.
- Non-patent Document 32 The prevalence of osteoporosis and kidney damage increases with age. There is also a large epidemiological study report that 85% of female osteoporosis patients have mild to moderate kidney damage (Non-patent Document 32). Therefore, it is important to provide an effective and safe drug for osteoporotic patients with renal impairment.
- the present inventors provide osteoporosis treatment / prevention agent / fracture suppression according to the present invention for all osteoporosis patient groups with normal renal function, osteoporosis patient group with mild renal dysfunction, and osteoporosis patient group with moderate renal dysfunction. / It was shown that the preventive agent is effective (Example 2). In addition, it became clear that the osteoporosis therapeutic agent and fracture inhibiting / preventing agent of the present invention are equivalent for all groups in terms of safety related to serum calcium.
- Normal renal function, disorder, and degree of disorder can be distinguished based on creatinine clearance. Specifically, it is possible to determine that creatinine clearance is 80 ml / min or more as normal renal function, 50 or more and less than 80 ml / min as mild renal dysfunction, and 30 or more and less than 50 ml / min as moderate renal dysfunction.
- the normal upper limit of serum calcium is 10.6 mg / ml, and 11.0 mg / ml exceeding this is a slightly high value.
- 11.0 mg / ml exceeding this is a slightly high value.
- 11.76% of patients with osteoporosis patients with moderate renal dysfunction had serum calcium exceeding 11.0 mg / ml, which was slightly higher after administration (Non-patent Document 32).
- Non-patent Document 32 the previous daily administration of PTH
- 11.76% of patients with osteoporosis patients with moderate renal dysfunction had serum calcium exceeding 11.0 mg / ml, which was slightly higher after administration.
- Non-patent Document 32 the present invention, as a result of administration of the osteoporosis treatment / prevention agent / fracture suppression / prevention agent of the present invention to an osteoporosis patient group having moderate renal dysfunction, patients with serum calcium exceeding 11.0 mg / ml are observed. No one was found at all examinations from the start to the end of administration (Example 2).
- an osteoporotic patient having mild renal dysfunction and / or an osteoporotic patient having moderate renal dysfunction can be preferably exemplified, and more preferably a primary osteoporotic patient having mild renal dysfunction and / or Or the primary osteoporosis patient which has moderate renal dysfunction can be illustrated.
- the race, age, sex, height, weight, etc. of the subject to which the drug administration or treatment method according to the present invention is to be applied are not particularly limited, but examples of the subject include osteoporosis patients, or fractures in osteoporosis It is desirable to apply the method of the present invention to an osteoporosis patient having many risk factors, or to administer the osteoporosis therapeutic agent or fracture inhibitor or preventive agent of the present invention.
- Risk factors for fractures in osteoporosis include age, sex, low bone density, history of fracture, smoking, alcohol consumption, steroid use, fracture family history, exercise, factors related to falls, bone metabolism markers, body weight, calcium intake, etc. (Non-Patent Document 10).
- an osteoporosis patient (or subject) that satisfies all the following conditions (1) to (3) is defined as a “high risk patient”.
- Age is 65 years or older
- the bone density is less than 80% of the average value of young adults and / or the degree of bone atrophy is I degree or more.
- bone density typically refers to the amount of bone mineral in the lumbar spine.
- the bone density can be indicated by the bone mineral content values of the radius, the second metacarpal bone, the femoral neck, and the radius.
- the average value of young adults means the average value of bone density between 20 and 44 years old.
- the bone density can be measured by a method known per se, such as a dual energy X-ray absorption measurement method, a photodensitometry method, a photon absorption measurement method, a quantitative CT method, and a quantitative ultrasonic method.
- the degree of bone atrophy means the degree of bone loss on X-ray.
- Bone atrophy is classified into no bone atrophy, bone atrophy degree I, bone atrophy degree II, and bone atrophy degree III. “No bone atrophy” in the degree of bone atrophy indicates a normal state, and specifically means a state in which the trabecular structure cannot be recognized because the trabeculae in the vertical and horizontal directions are dense.
- the degree of bone atrophy I means that the vertical trabeculae are conspicuous. Typically, the vertical trabeculae look thin but are densely arranged, and the vertebral endplates also stand out. means.
- the bone atrophy degree II in the bone atrophy means a state in which the vertical trabecular bone is rough, the vertical trabecular bone is thick, the arrangement is rough, and the vertebral endplate is also light.
- the degree of bone atrophy III means that the longitudinal trabecular bone is also obscured, the vertebral body shadow shows a blurred feeling as a whole, and the difference from the intervertebral disk shadow decreases (osteoporosis treatment, 5/3, July 2006, “Diagnosis of osteoporosis by simple radiographs”).
- the degree of bone atrophy can be determined from, for example, a lumbar lateral X-ray image.
- the number of vertebral fractures referred to in the present invention can be easily measured by, for example, the method of Genant et al. (Non-Patent Document 14).
- a fracture at a site other than the vertebral body can be easily confirmed using, for example, an X-ray film.
- the method of the present invention it is particularly preferable to apply the method of the present invention to a high-risk patient or administer the osteoporosis treatment or prevention agent or fracture suppression or prevention agent of the present invention (Example 1).
- the method of the present invention is applied to a patient (subject) corresponding to at least one of the following (1) to (6), and the osteoporosis treatment or prevention agent of the present invention according to the method is applied.
- the osteoporosis treatment or prevention agent of the present invention according to the method is applied.
- the osteoporosis treatment / prevention agent or fracture-suppressing / prevention agent (hereinafter sometimes simply referred to as “this agent”) according to the present invention can take various preparation forms.
- the agent can be used as an injection or the like with PTH alone or a conventional pharmaceutically acceptable carrier. An injection is preferred as the dosage form of the agent.
- PTH when the agent is an injection, PTH is dissolved in an appropriate solvent (sterilized water, buffer solution, physiological saline, etc.), filtered with a filter and / or sterilized by other appropriate methods, and then It can be prepared by filling a sterile container.
- necessary additives for example, excipients, stabilizers, solubilizers, antioxidants, soothing agents, tonicity agents, pH adjusters, preservatives, etc.
- additives include sugars, amino acids, and sodium chloride.
- mannitol, glucose, sorbitol, inositol, sucrose, maltose, lactose, and trehalose may be added in an amount of 1 weight or more (preferably 50 to 1000 weight) with respect to 1 weight of PTH. preferable.
- saccharide and sodium chloride are used as additives, it is preferable to add 1/1000 to 1/5 weight (preferably 1/100 to 1/10 weight) of sodium chloride per 1 weight of saccharide.
- the agent when the agent is an injection, the agent may be solidified by means such as freeze-drying (lyophilized preparation, etc.), and may be dissolved in a suitable solvent at the time of use.
- the agent when the agent is an injection, the agent may be a solution that is dissolved in advance.
- the drug is contained in a package that states that 100 to 200 units of human PTH (1-34) should be administered every other week as an osteoporosis therapeutic agent and a fracture suppression / prevention agent. Or it can be set as the chemical
- Example 1 For male and female patients diagnosed with primary osteoporosis (Non-patent Document 12), 5 or 100 units of teriparatide acetate prepared by Takai's method (Patent Documents 4 to 5 and Non-patent Document 11), respectively, are given each week. Were intermittently administered once subcutaneously (each 5 or 100 unit administration group). The activity of teriparatide acetate was measured according to a paper by Marcus et al. (Non-patent Document 9).
- a freeze-dried preparation containing 5 or 100 units of teriparatide acetate in one vial was dissolved in 1 mL of physiological saline at the time of use, and the whole solution was administered. Furthermore, calcium tablets (containing 500 mg of precipitated calcium carbonate [200 mg as calcium] in one tablet) were administered once a day in both 5 or 100 unit administration groups.
- Osteoporosis patients were classified and compared according to the conditions shown in Table 1 according to the status of fracture risk factors shown in Non-Patent Document 13.
- a high-risk patient (sometimes simply referred to as a high-risk person) is defined as having all three factors: age, preexisting vertebral fracture, bone density, or bone atrophy. It was supposed to be.
- the patient background is as shown in Tables 2 and 3, and no statistically significant difference was found between the backgrounds of both groups (p ⁇ 0.05).
- calcitonin preparations active vitamin D 3 preparations, vitamin K preparations, ipriflavone preparations, bisphosphonate preparations, estrogen preparations, anabolic hormone preparations, calcium preparations prescribed by doctors (however, once a day, 2 Concomitant use of other drugs that may affect bone metabolism was prohibited.
- confirmation of lumbar bone density and occurrence of fracture was performed. The lumbar bone density was measured at the beginning and every 6 months after the start of the measurement of the second to fourth lumbar bone densities using the dual energy X-ray absorption measurement method (DXA method).
- DXA method dual energy X-ray absorption measurement method
- X-ray imaging of the front and side surfaces from the 4th thoracic vertebra to the 5th lumbar vertebra was performed at the start and every 6 months thereafter, referring to the method of Genant et al.
- New vertebral fractures were evaluated by comparing X-ray films at the beginning and at the following time points.
- evaluation was performed by confirmation with an X-ray film.
- blood was collected at the start of administration and during the administration period, and general laboratory values including calcium concentration were measured.
- the administration period in high-risk individuals is 85.1 ⁇ 20.8 weeks in the 5-unit administration group, The 100 unit administration group had 83.7 ⁇ 19.8 weeks, and no significant difference was observed between the two groups (p ⁇ 0.05).
- the low-risk subjects were 72.7 ⁇ 19.4 weeks in the 5-unit administration group and 88.3 ⁇ 21.3 weeks in the 100-unit administration group, and there was no significant difference between the two groups (p ⁇ 0.05).
- Tables 4 and 5 show changes in lumbar bone density by administration group for high-risk and low-risk individuals.
- the bone density of the 100 unit administration group was significantly higher than that at the start of administration, and was significantly higher than the 5 unit administration group (p ⁇ 0). .05).
- the low-risk individuals no significant difference was observed in the comparison with the start of administration and between the groups (p> 0.05).
- Tables 6 and 7 show the results of the occurrence of new vertebral fractures by high-risk and low-risk subjects by treatment group.
- the 100-unit administration group had significantly lower occurrence of fractures than the 5-unit administration group (p ⁇ 0.05).
- there was no significant difference between groups in low-risk individuals (p> 0.05).
- Tables 8 and 9 show the results of occurrence of new vertebral fractures every 26 weeks by administration group for high-risk and low-risk individuals.
- the 100-unit administration group suppressed the occurrence of fractures after 26 weeks compared to the 5-unit administration group.
- Tables 10 and 11 show the results of fractures occurring at sites other than the vertebral body in each treatment group for high-risk and low-risk individuals.
- high-risk individuals the fracture rate in the 100-unit group was significantly lower than that in the 5-unit group.
- Fig. 1 shows the results of changes in serum calcium concentration by administration group for high-risk and low-risk individuals.
- hypercalcemia was not observed in all cases except for one case that was higher than before the start of drug administration in the 5-unit administration group of low-risk individuals.
- the tendency for serum calcium to rise was not recognized.
- teriparatide acetate 100 units once a week to a high-risk patient with a novel fracture of the present invention can be a useful osteoporosis therapeutic agent and a fracture inhibiting or preventing agent.
- teriparatide acetate of the present invention does not cause hypercalcemia at any dose, and is useful compared to the daily administration of teriparatide acetate already known. It was thought that there was.
- Example 2 Test drug (1 vial; 200 vials of teriparatide acetate contained in one vial) prepared by Takai's method (Patent Documents 4 to 5, Non-Patent Document 11) for high-risk male and female patients diagnosed with primary osteoporosis Lyophilized formulation for injection) or control drug (1 vial; placebo formulation substantially free of teriparatide acetate in 1 vial) dissolved in 1 mL of physiological saline each time, once a week for 72 weeks was intermittently administered subcutaneously.
- This calcium preparation is a soft chewable preparation containing 610 mg of calcium, 400 IU of vitamin D 3 and 30 mg of magnesium in 2 tablets, and contains precipitated calcium carbonate, magnesium carbonate, cholecalciferol (vitamin D 3 ) and the like as ingredients, It is commercially available under the trade name of “New Karushichu (trademark) D 3 ” (distributor: Daiichi Sankyo Healthcare, manufacture / seller: Nitto Pharmaceutical Co., Ltd.).
- the above patients are all outpatients capable of walking independently and do not meet any of the following criteria (1) to (19).
- (1) A patient diagnosed with secondary osteoporosis for a predetermined cause.
- the predetermined causes are endocrine (hyperthyroidism, gonadal dysfunction, Cushing syndrome), nutrition (scurvy, other (protein deficiency, vitamin A or D excess)), drug (corticosteroid, Methotrexate (MTX), heparin, aromatase inhibitor, GnRH agonist), immobility (systemic (bed rest, paraplegia, space flight), locality (after fracture etc.)), congenital (bone dysplasia, Marfan) Syndrome etc.) and other (rheumatoid arthritis, diabetes, liver disease, gastrointestinal disease (gastrectomy), etc.).
- endocrine hyperthyroidism, gonadal dysfunction, Cushing syndrome
- nutrition scurvy, other (protein deficiency, vitamin A or D excess)
- drug corticosteroid
- Patients with a history of hypersensitivity to PTH preparations (9) Patients with bone budget disease. (10) Patients with a history of malignant bone tumor or a history of malignancy within the past 5 years. (11) Patients with multiple exostosis. (12) A patient with a history of external radiation therapy to the skeleton or a radiation tissue irradiation therapy history. (13) A patient whose serum calcium level is 11.0 mg / dL or more. (14) Patients whose alkaline phosphatase value is more than twice the upper limit of the reference value. (15) Patients with severe kidney disease, liver disease or heart disease. The criteria for each disease are as follows.
- Renal disease Serum creatinine level is 2 mg / dL or higher
- Liver disease AST (GOT) or ALT (GPT) level is 2.5 times the upper limit of the reference value or 100 IU / L or higher
- Heart disease “Severity of side effects of drugs Judgment criteria (June 29, 1992 Yakuyasu No. 80) "grade 2" shown in the reference.
- Lumbar vertebra bone density was measured at the start and every 24 weeks after the start of the measurement of the second to fourth lumbar vertebra bone density using the dual energy X-ray absorption measurement method (DXA method).
- DXA method dual energy X-ray absorption measurement method
- the femur bone density was measured by initiating the proximal part of the femur 20 degrees using a dual energy X-ray absorption measurement method (DXA method), and measuring only the left side every 24 weeks thereafter.
- DXA method dual energy X-ray absorption measurement method
- DXA geometry was evaluated by femur bone density data at the start of measurement measured by the attending physician and every 24 weeks thereafter.
- CT geometry was measured 48 weeks later and 72 weeks later at the start of measurement of the proximal femur using multi-slice CT.
- X-ray imaging of the front and sides from the 4th thoracic vertebra to the 4th lumbar vertebra was performed at the start and every 24 weeks thereafter, referring to the method of Genant et al. New and exacerbated vertebral fractures were evaluated by comparing X-ray films at the beginning and at subsequent time points.
- the X-ray film was used for confirmation (DXA, bone geometry, new and exacerbated vertebral fractures were determined collectively at the center, and non-vertebral fractures were determined by the attending physician using the X-ray film).
- test drug Efficacy of test drug on primary osteoporosis patients taking steroids
- the effect of test drug administration on primary osteoporosis patients taking steroids was tested.
- the test drug is effective for primary osteoporosis patients taking steroids.
- Diabetic osteoporosis whose primary disease is diabetes, is one of the secondary osteoporosis, but the effect of the test drug on primary osteoporosis patients with diabetes as a complication is that the test drug is effective against diabetic osteoporosis. May also indicate the possibility of a therapeutic effect.
- the evaluation results for the bone density change rate are shown in the table below.
- the increase in the bone density was remarkable 48 weeks after the administration of the test drug, even in patients with any other history of osteoporosis treatment, and in particular, other osteoporosis
- the therapeutic agents were calcium L-aspartate, elcatonin, alphacalcidol, menatetrenone and calcitriol, a significant increase in lumbar bone density was observed at an early stage of 24 weeks after administration.
- osteoporosis treatments are calcium L-aspartate and elcatonin
- the other osteoporosis therapeutic agent is elcatonin
- the bone density in the proximal femur has already increased significantly from 24 weeks after administration of the test drug.
- the following table shows the results of detailed evaluation of the effects of the history of other osteoporosis treatments on the efficacy of the test drug for each of these other osteoporosis treatments in terms of the incidence of new vertebral fractures.
- the table shows the results of detailed evaluation of the effects of the history of other osteoporosis treatments on the efficacy of the test drug for each of these other osteoporosis treatments in terms of the incidence of new vertebral fractures.
- H-1 Distribution of background factors for each patient group (details) “Normal (80 ⁇ )” is a group of osteoporosis patients with normal renal function, “Mild improvement (50 ⁇ ⁇ 80)” is a group of osteoporosis patients with mild renal dysfunction, and “Moderate” is a group of osteoporosis patients with moderate renal dysfunction. impirment ( ⁇ 50) ”. Further, the test drug administration group was designated as “PTH200 group”, and the control drug administration group as “P group”. In addition, an osteoporosis patient group having mild renal dysfunction and an osteoporosis patient group having moderate renal dysfunction may be collectively referred to as “Abnormal ( ⁇ 80)”. Each patient was classified into the above groups based on their creatinine clearance. Specifically, creatinine clearance of 80 ml / min or more was regarded as normal renal function, 50 or more and less than 80 ml / min as mild renal dysfunction, and 30 or more and less than 50 ml / min as moderate renal dysfunction.
- test drug has an effect of increasing the lumbar bone density in the osteoporosis patient group with normal renal function, the osteoporosis patient group with mild renal dysfunction, and the osteoporosis patient group with moderate renal dysfunction.
- test drug safety for each patient group (incidence of side effects)
- the test drug is the control for any group
- the expression rate was about twice that of the drug. That is, it became clear that the test drug was equivalent to all groups in terms of safety regarding the incidence of side effects.
- the incidence of new vertebral fractures every six months was almost constant at about 5% in all sections in the P group.
- the incidence of each section decreased as the administration period became longer, and no new vertebral fracture occurred after 48 weeks.
- the incidence of new vertebral fractures in the PTH200 group is lower than that in the P group within 24 weeks, 24 weeks to 48 weeks, and 48 weeks to 72 weeks, and the relative risk reduction rate with respect to placebo (relative risk reduction; RRR). ) Increased with continued administration.
- RRR relative risk reduction
- the incidence of vertebral fractures (new + exacerbation) after 72 weeks according to the Kaplan-Meier estimation method was 3.5% in the PTH200 group and 16.3% in the P group. The incidence of units was lower than the placebo group (logrank test, p ⁇ 0,0001). In addition, this drug 200 units reduced the risk of vertebral fracture (new + exacerbation) by 78.6% after 72 weeks compared to placebo.
- the incidence in the PTH200 group is lower than that in the P group within 24 weeks, 24 to 48 weeks, and 48 to 72 weeks.
- FIG. 4 shows the results of testing the fluctuation of urinary calcium level and corrected serum calcium level when a test drug or control drug is administered to a patient for 72 weeks at a frequency of once a week (FIGS. 4 to 5).
- the mean value (and median) of the urinary calcium value change rate was 3.2% ( ⁇ 14.7%) in the PTH200 group and 23.6% (1.6%) in the P group after 72 weeks at the start.
- the PTH 200 group showed a decreasing trend compared to the P group.
- the corrected serum calcium level was in the range of 9.3 to 9.6 mg / dL on average in both groups.
- the corrected serum calcium after administration in the PTH200 group is 8.5 mg / dI (after 48 and 72 weeks) at the minimum, 11.6 mg / dl (after 4 weeks) at the maximum, and the minimum is 8 in the P group. .5 mg / dL (after 4 weeks), 12. 1 mg / dI (after 12 weeks). There was no significant change in either group. There were no adverse events of serum calcium elevation or reduction in this study. In this study, the PTH 200 group did not show any expression of hypercalcemia or hypercalciuria compared to the P group.
- the osteoporosis treatment / prevention and fracture suppression / prevention method of the present invention are excellent in both efficacy, effect and safety, and the fracture suppression method of the present invention is highly safe, both for the treatment of osteoporosis and the like and suppression / prevention of fractures.
- This is an innovative medical technology that contributes greatly. Therefore, the osteoporosis treatment / prevention agent and the fracture suppression / prevention agent of the present invention for this purpose are extremely useful in the pharmaceutical industry.
Abstract
Description
〔1〕カルシウム剤と併用され、かつ、1回当たり100~200単位のPTHが週1回投与されることを特徴とする、PTHを有効成分として含有する骨粗鬆症治療ないし予防剤。
〔2〕併用されるカルシウム剤が週1回以上投与されることを特徴とする、前記〔1〕の骨粗鬆症治療ないし予防剤。
〔3〕併用されるカルシウム剤が、カルシウムとして1日あたり200~800mg投与されることを特徴とする、前記〔1〕または〔2〕の骨粗鬆症治療ないし予防剤。
〔4〕前記PTHがヒトPTH(1-34)である、前記〔1〕~〔3〕のいずれかである骨粗鬆症治療ないし予防剤。
〔5〕24週または48週を超過する期間にわたり投与するための、前記〔1〕~〔4〕いずれかに記載の骨粗鬆症治療ないし予防剤。
〔6〕下記(1)~(3)の全ての条件を満たす骨粗鬆症患者を治療するための、前記〔1〕~〔5〕のいずれかである骨粗鬆症治療ないし予防剤;
(1)年齢が65歳以上である
(2)既存の骨折がある
(3)骨密度が若年成人平均値の80%未満である、および/または、骨萎縮度が萎縮度I度以上である。
〔7〕ステロイドを起因とする続発性骨粗鬆症、あるいは、糖尿病性骨粗鬆症を治療ないし予防するための、前記〔1〕~〔6〕のいずれか1に記載の骨粗鬆症治療ないし予防剤。
〔8〕 下記(1)~(8)の少なくともいずれか1の疾病を合併症として有する骨粗鬆症を治療ないし予防するための、〔1〕~〔6〕のいずれか1に記載の骨粗鬆症治療ないし予防剤;
(1)糖尿病、
(2)高血圧、
(3)高脂血症、
(4)関節痛、
(5)変形性脊椎症、
(6)変形性腰痛症、
(7)変形性股関節症、
(8)変形性顎関節症。
〔9〕 下記(1)~(6)の少なくともいずれか1つの骨粗鬆症治療薬の投与歴がある骨粗鬆症患者に投与するための、〔1〕~〔6〕のいずれか1に記載の骨粗鬆症治療ないし予防剤;
(1)L-アスパラギン酸カルシウム
(2)アルファカルシドール、
(3)エルカトニン、
(4)塩酸ラロキシフェン、
(5)メナテトレノン、
(6)乳酸カルシウム
〔10〕 軽度腎障害または中程度腎障害を有する骨粗鬆症患者に投与するための、〔1〕~〔6〕のいずれか1に記載の骨粗鬆症治療ないし予防剤。
〔11〕前記PTHがヒトPTH(1-34)である、前記〔6〕~〔10〕のいずれか1の骨粗鬆症治療ないし予防剤。
〔12〕前記PTHを有効成分として含有する骨粗鬆症治療剤が皮下注射剤である、前記〔6〕~〔11〕のいずれかに記載の骨粗鬆症治療ないし予防剤。
〔13〕 前記〔1〕~〔12〕のいずれか1に記載の骨粗鬆症治療ないし予防剤と下記(1)~(6)の少なくともいずれか1つの薬剤からなる合剤または医療用キット。
(1)メトクロプラミド、
(2)ドンペリドン、
(3)ファモチジン、
(4)クエン酸モサプリド、
(5)ランソプラゾール、
(6)六神丸。
〔14〕1回当たり100~200単位のPTHが週1回投与されることを特徴とする、PTHを有効成分として含有する骨粗鬆症治療ないし予防剤であって、下記(1)~(3)の全ての条件を満たす骨粗鬆症患者を治療するための、骨粗鬆症治療ないし予防剤;
(1)年齢が65歳以上である
(2)既存の骨折がある
(3)骨密度が若年成人平均値の80%未満である、および/または、骨萎縮度が萎縮度I度以上である。
〔15〕1回当たり100~200単位のPTHが週1回投与されることを特徴とする、PTHを有効成分として含有する、骨折の危険性の高い骨粗鬆症治療ないし予防剤。
〔16〕1回当たり100~200単位のPTHが週1回投与されることを特徴とする、PTHを有効成分として含有する骨粗鬆症治療ないし予防剤であって、ステロイドを起因とする続発性骨粗鬆症、あるいは、糖尿病性骨粗鬆症を治療ないし予防するための、骨粗鬆症治療ないし予防剤。
〔17〕1回当たり100~200単位のPTHが週1回投与されることを特徴とする、PTHを有効成分として含有する骨粗鬆症治療ないし予防剤であって、軽度腎障害または中程度腎障害を有する骨粗鬆症患者に投与するための、骨粗鬆症治療ないし予防剤。
〔18〕カルシウム剤と併用され、かつ、1回当たり100~200単位のPTHが週1回投与されることを特徴とする、PTHを有効成分として含有する骨折抑制ないし予防剤。
〔19〕併用されるカルシウム剤が週1回以上投与されることを特徴とする、前記〔18〕の骨折抑制ないし予防剤。
〔20〕併用されるカルシウム剤が、カルシウムとして1日当たり200~800mg投与されることを特徴とする、前記〔18〕または〔19〕の骨折抑制ないし予防剤。
〔21〕前記PTHがヒトPTH(1-34)である、前記〔18〕~〔20〕のいずれかである骨折抑制剤。
〔22〕下記(1)~(3)の全ての条件を満たす対象者に投与するための、前記〔18〕~〔21〕のいずれかである骨折抑制ないし予防剤;
(1)年齢が65歳以上である
(2)既存の骨折がある
(3)骨密度が若年成人平均値の80%未満である、および/または、骨萎縮度が萎縮度I度以上である。
〔23〕前記PTHがヒトPTH(1-34)である、前記〔22〕の骨折抑制ないし予防剤。
〔24〕前記PTHを有効成分として含有する骨折抑制ないし予防剤が皮下注射剤である、前記〔22〕または〔23〕の骨折抑制ないし予防剤。
〔25〕骨折抑制ないし予防剤が多発骨折抑制ないし多発骨折予防剤である、前記〔18〕~〔24〕のいずれか1に記載の骨折抑制ないし予防剤。
〔26〕骨折抑制ないし予防剤が増悪骨折抑制ないし増悪骨折予防剤である、前記〔18〕~〔25〕のいずれか1に記載の骨折抑制ないし予防剤。
〔27〕前記〔14〕または〔15〕の骨粗鬆症治療ないし予防剤であって、ステロイドを起因とする続発性骨粗鬆症、あるいは、糖尿病性骨粗鬆症を治療ないし予防するための、骨粗鬆症治療ないし予防剤。
〔28〕前記〔14〕または〔15〕の骨粗鬆症治療ないし予防剤であって、軽度腎障害または中程度腎障害を有する骨粗鬆症患者に投与するための、骨粗鬆症治療ないし予防剤。
〔29〕前記〔27〕の骨粗鬆症治療ないし予防剤であって、軽度腎障害または中程度腎障害を有する骨粗鬆症患者に投与するための、骨粗鬆症治療ないし予防剤。
〔30〕前記〔16〕の骨粗鬆症治療ないし予防剤であって、軽度腎障害または中程度腎障害を有する骨粗鬆症患者に投与するための、骨粗鬆症治療ないし予防剤。
〔31〕上記〔1〕~〔30〕のいずれかに記載の治療剤、予防剤、薬剤、合剤、またはキットを用いる、予防または治療方法。
本発明の有効成分であるPTH(以下、単に「PTH」ということもある。)は、ヒト副甲状腺ホルモンであるヒトPTH(1-84)、及び、ヒトPTH(1-84)と同等又は類似の活性を有する分子量約4,000~10,000程度のペプチド類を包含する。
本発明者らは、カルシウム剤併用下でのPTHに関し、骨折発生を主要評価項目とした二重盲検比較臨床試験を実施した結果、その効果は24または26週後という早期から発現され、さらに、有害事象として高カルシウム血症が確認されなかった(実施例1~2)。従って、本発明に係る骨粗鬆症治療剤又は骨折抑制/予防剤は、他の薬剤と併用することを一つの特徴とする。ここで、他の薬剤との併用とは、本発明に係る骨粗鬆症治療剤又は骨折抑制/予防剤と本剤とは別のある薬剤(他の薬剤)を併用することを意味する。
カルシウムのみとの併用、
カルシウムならびにビタミンD(その誘導体を含む)および/またはマグネシウムのみとの併用、
も好ましく例示できる。よって、他の薬剤の具体的様態として、カルシウム剤を例示でき、好ましくは、
(1)カルシウムを薬効成分として含むカルシウム剤、
(2)カルシウム、ビタミンD(その誘導体を含む)およびマグネシウムをそれぞれ薬効成分として含むカルシウム剤を好ましく例示できる。
本発明に係る骨粗鬆症治療/予防剤又は骨折抑制/予防剤の投与期間は特に限定されず、患者に応じた医師の処方等により適宜決定することができる。本発明者らは、投与期間を156または72週間として、骨折発生を主要評価項目とした二重盲検比較臨床試験を実施した。本試験において、当該投与による有意な骨折抑制効果を確認でき、その効果は24または26週後という早期から発現した(実施例1~2)。さらに、投与後48週を超えてからの新規椎体骨折は認められなかった(実施例2)。従って、投与期間として、24週以上、26週以上、48週以上、52週以上、72週以上、または78週以上を例示することができ、最も好ましくは78週以上である。また、本試験において、有害事象として高カルシウム血症は確認されなかった(実施例1)。
本発明者らは、1回当たり100または200単位のPTHを用いた二重盲検比較臨床試験を実施した結果、当該投与による有意な骨折抑制効果と24または26週後という早期からの効果の発現を認め、一方で有害事象としての高カルシウム血症は確認されなかった(実施例1~2)。
本発明者らは、1週間に1回の頻度でPTH投与する二重盲検比較臨床試験を実施した結果、当該投与による有意な骨折抑制効果と24または26週後という早期からの効果の発現を認め、一方で有害事象としての高カルシウム血症は確認されなかった(実施例1~2)。従って、本発明は、その投与間隔を隔週とすることを特徴の一つとする。
本発明の骨粗鬆症治療/予防剤・骨折抑制/予防剤は、その製剤形態に応じた適当な投与経路により投与され得る。例えば、本発明の骨粗鬆症治療ないし予防剤或いは骨折抑制ないし予防剤が注射剤の場合には、静脈、動脈、皮下、筋肉内などに投与され得る。本発明者らは、PTHを皮下注射した結果、優れた効能・効果及び安全性を示すことを立証した(実施例1~2)。従って、本発明は、その投与経路として皮下投与経路を好ましく例示可能である。
本発明に係る骨粗鬆症は特に限定されず、原発性骨粗鬆症及び続発性骨粗鬆症のいずれをも含む。原発性骨粗鬆症としては、例えば、退行期骨粗鬆症(閉経後骨粗鬆症及び老人性骨粗鬆症)、特発性骨粗鬆症(妊娠後骨粗鬆症、若年性骨粗鬆症など)が例示される。続発性骨粗鬆症は、特定の疾病や特定の薬剤等の原因により誘発される骨粗鬆症であり、例えば、特定の薬剤、関節リウマチ、糖尿病、甲状腺機能亢進症、性機能異常、不動性、栄養性、その他先天性疾患などが原因として挙げられる。特定の薬剤として、例えば、ステロイドが例示される。本発明に係る骨粗鬆症として骨折の危険性の高い骨粗鬆症を好ましく例示できる。骨折の危険性の高い骨粗鬆症への本発明の適応は下記の高リスク患者への本発明の適応を意味する。
1) 糖尿病性の骨減少症示すsreptozotocin処理ラットに対してhPTHを投与することによって、cancelous enveropeにおいて『骨量』、『骨梁幅』、『類骨表面』、『石灰化面』、『骨石灰化速度』、『骨形成速度』の増加が見られ、さらに、endocortical envelopeでは『類骨表面』、『石灰化面』、『骨石灰化速度』、『皮質骨厚』の増加が見られたことが報告されている(非特許文献21)。ただし、本ラットは、他の原因による骨減少症ラットと異なり、吸収面の顕著な減少は見られていない。
2) sreptozotocin処理ラットに対して8週間に渡ってPTHを投与した結果、海面骨量とターンオーバーの回復を認めたことが報告されている(非特許文献22)。
3) 培養細胞における実験では高濃度のグルコースに曝露されるとhPTH(1-34)に対する反応が落ちる(PTHの効きが悪くなる)ことが報告されている(非特許文献20)。
長管骨(四肢を構成する長形状の骨)の一つである大腿骨は、その骨端が関節軟骨と接触してその他滑膜や半月板とともに膝関節を形成している。その接触面は厚さ数ミリ程度の軟骨に覆われる関節面と称される。膝関節痛の原因となる疾病として例えば変形性膝関節症が例示される。
加齢等の何らかの原因によって正常な椎体骨量が減少すると椎体が不安定化する。不安定化は終板の変形によって始まる。椎体の不安定化とは、具体的には、終盤の薄化や終盤孔(ハバース管)の拡大である。その不安定化が進むと、椎間板の終盤孔への進入や椎間板狭小化が見られる。さらに症状が進めば、椎骨同士の衝突による骨棘(こつきょく)生成にいたる。このような脊椎の変性が変形性脊椎症といわれる疾病である。変形性脊椎症になると、椎間が安定化して椎間板の進入に起因する痛みや周辺の筋肉膨張による痛みなどが生じることになる。
変形性股関節症は、関節に対する血流不良や極度の加重や酷使を理由として、股関節を形成している臼蓋と大腿骨頭の接触面の関節軟骨が摩耗、変性、不可逆性の変化を起こした状況である。変形性股関節症患者の大腿骨皮質骨面積は健常者のそれと比較して有意に大きい(非特許文献18)。大腿骨皮質骨面積の増大は、大腿骨の外側への肥大化を意味し、従ってこれが変形性股関節症の発症または増悪に関与している可能性がある。本発明のように大腿骨の内側への肥厚化をさせる場合には、大腿骨の外側への肥大化をさせることはないので、変形性股関節症の発症または増悪リスクを増大させない可能性がある。変形性顎関節症は顎関節の変形を主徴候とするものであるが、皮質骨の肥厚が診断所見の一つとなっている(非特許文献19)。従って、皮質骨のさらなる外側への肥大化が症状を悪化または発症させる可能性がある。本発明のように骨の内側へ肥厚させる場合には、このような変形性顎関節症の発症または増悪リスクを増大させない可能性が推定される。
(1)年齢が65歳以上である
(2)既存骨折がある
(3)骨密度が若年成人平均値の80%未満である、および/または、骨萎縮度が萎縮度I度以上である。
(1)気管支喘息、発疹(紅班、膨疹等)などの過敏症を起こしやすい体質の患者
(2)高カルシウム血症患者
(3)妊婦または妊娠している可能性のある婦人
(4)甲状腺機能低下症または副甲状腺機能亢進症の患者
(5)過去に薬物過敏症を呈したことのある患者
(6)心疾患、肝疾患、腎障害など重篤な合併症を有する患者
従って、本発明においては、上記高リスク患者であって、かつ、上記(1)~(6)全てに該当しない骨粗鬆症患者等を適用対象とすることが好ましい。
本発明に係る骨粗鬆症治療/予防剤又は骨折抑制/予防剤(以下、単に「本剤」ということもある。)は、種々の製剤形態をとり得る。一般的には、本剤は、PTH単独又は慣用の薬学的に許容される担体とともに注射剤等とされ得る。本剤の剤形として注射剤が好ましい。
原発性骨粗鬆症と診断された男女の患者(非特許文献12)に対して、Takaiの方法(特許文献4~5、非特許文献11)により調製した、5あるいは100単位のテリパラチド酢酸塩をそれぞれ週に1回間欠的に皮下投与した(それぞれを5あるいは100単位投与群とする)。なお、テリパラチド酢酸塩の活性測定はMarcusらの論文(非特許文献9)に従った。
原発性骨粗鬆症と診断された男女の高リスク患者に対して、Takaiの方法(特許文献4~5、非特許文献11)により調製した被験薬(1バイアル;1バイアルにテリパラチド酢酸塩200単位を含む注射用凍結乾燥製剤)または対照薬(1バイアル;1バイアルにテリパラチド酢酸塩を実質的に含まないプラセボ製剤)をそれぞれ生理的食塩水1mLで用時溶解して72週間にわたり週に1回の頻度で間欠的に皮下投与した。
(1)所定の原因により続発性骨粗鬆症と診断された患者。ここで所定の原因とは、内分泌性(甲状腺機能亢進症、性腺機能不全、Cushing症候群)、栄養性(壊血病、その他(タンパク質欠乏、ビタミンAまたはD過剰))、薬物(副腎皮質ホルモン、メトトレキサート(MTX)、へパリン、アロマターゼ阻害剤、GnRHアゴニスト)、不動性(全身性(臥床安静、対麻痺、宇宙飛行)、局所性(骨折後等))、先天性(骨形成不全症、Marfan症候群等)、その他(関節リウマチ、糖尿病、肝疾患、消化器疾患(胃切除)等)を意味する。
(2)骨粗鬆症以外の骨量減少を呈する所定の疾患を有する患者。ここで所定の疾患とは、各種の骨軟化症、原発性、続発性副甲状腺機能亢進症、悪性腫瘍の骨転移、多発性骨髄腫、脊椎血管腫、脊椎カリエス、化膿性脊椎炎、その他を意味する。
(3)椎体の強度に影響を及ぼすと考えられる所定のX線所見を有する患者。ここで所定とは6個以上の連続した椎体が架橋を形成している、椎体周辺の靱帯に著しい骨化が認められる、脊椎に著しい脊柱変形を有する、椎体の手術が施行されている、ことを意味する。
(4)胸腰椎体全体を覆うコルセットを装着している患者。
(5)同意取得前52週(364日)以内にビスホスフォネート製剤の投与を受けた患者。
(6)同意取得日に以下の骨粗鬆症治療薬の投与を受けている患者(ただし、治療開始までに8週(56日)以上の休薬(ウォッシュアウト)が可能ならば、対象として選択可とする)。カルシトニン製剤、活性型ビタミンD3製剤、ビタミンK製剤、イプリフラボン製剤、エストロゲン製剤、SERM製剤、蛋白同化ホルモン製剤。
(7)気管支喘息、発疹(紅斑、膨疹等)等の過敏症状を起こしやすい体質の患者。
(8)PTH製剤に対して過敏症の既往歴のある患者。
(9)骨バジェット病の患者。
(10)悪性骨腫瘍の既往または過去5年以内に悪性腫瘍の既往のある患者。
(11)多発性外骨腫症の患者。
(12)骨格への放射線外照射療法歴または放射線組織内照射療法歴を有する患者。
(13)血清カルシウム値が11.0mg/dL以上の患者。
(14)アルカリフォスファターゼ値が基準値上限の2倍以上の患者。
(15)重篤な腎疾患、肝疾患または心疾患を有する患者。各疾患の基準は次の通り。
腎疾患:血清クレアチニン値が2mg/dL以上
肝疾患:AST(GOT)またはALT(GPT)値が基準値上限の2.5倍以上または100IU/L以上
心疾患:「医薬品の副作用の重篤度分類基準について(平成4年6月29日薬安発第80号)」に示すグレード2を参考に判断する。
(16)問診の信頼性が低いと判断された患者(少なくとも認知症の患者は必ず除外する)。
(17)他の治験薬を同意取得前26週(182日)以内に投与された患者。
(18)過去に治験でPTH製剤の投与を受けた患者。
(19)その他、治験責任(分担)医師が本治験の実施にあたり不適当と判断した患者。
薬剤の投与が禁止された。
(1) テリパラチド酢酸塩以外の骨粗鬆症治療薬(具体的には、ビスホスフォネート製剤、
カルシトニン製剤、活性型ビタミンD3製剤、カルシウム製剤(ただし、上記の1日1回
夕食後に服薬するカルシウム製剤は除く)、ビタミンK製剤、イプリフラボン製剤、エストロゲン
製剤、SERM製剤、蛋白同化ホルモン製剤)
(2) 副腎皮質ホルモン製剤(ただし、筋注、静注または経口投与、ブレドニゾロン換算で、
1週間平均として5mg/日を超える場合、1日投与量として10mg/日を超える場合、
または総投与量が450mgを超える場合)
(3) アロマターゼ阻害剤
(4) GnRHアゴニスト
(5) 他の治験薬
ここで椎体多発骨折を新規の2箇所以上の椎体骨折と定義して、投与72週後における被験薬投与群(n=261)と対照薬投与群(n=281)それぞれにおける椎体多発骨折発生比率(例数)を比較したところ、対照薬投与群は2.1%(6例)、被験薬投与群は0.8%(2例)であった。すなわち、被験薬は椎体多発骨折に対して抑制ないし予防効果を有することが示された。
骨折発生個数別の症例数を下記表に示す。
ステロイドを服用する原発性骨粗鬆症患者に対する被験薬投与の効果を試験した。その結果、下記の表のとおり、ステロイドを服用する原発性骨粗鬆症患者に対して被験薬が有効であることが示された。
大腿骨3部位(大腿骨頚部、大腿骨転子間部、大腿骨骨幹部)に対する被験薬の効果を一般的なCT法に準じて試験した。その結果、下記の表のように、大腿骨各部位に対して被験薬は有効であることが示された。
上記患者の中には合併症を有している者もいる。そこで、合併症の種類(糖尿病、高血圧、高脂血症)やその有無が被験薬効果に与える影響を評価した。その結果、下記の表の通り、これら合併症の種類や有無に関わらず、さらに投与後24週時点以降において、被験薬は新規椎体骨折発生を抑制することが明らかになった。
前述のように、上記患者に対して、治験への同意時から治験終了時までの間、テリパラチド酢酸塩以外の骨粗鬆症治療薬の投与は原則的に禁止された。しかし、治験への同意時以前においては、所定の条件の下、他の骨粗鬆症治療薬の服薬を受けている患者も存在していた。そこで、当該他の骨粗鬆症治療薬の服薬歴が被験薬有効性に与える影響を、新規椎体骨折発生率および骨密度変化率の観点から評価した。
腎機能正常の骨粗鬆症患者群、軽度腎機能障害を有する骨粗鬆症患者群、および中等度腎機能障害を有する骨粗鬆症患者群に対する被験薬の有効性及び安全性を試験した。
腎機能正常の骨粗鬆症患者群を「Normal(80≦)」、軽度腎機能障害を有する骨粗鬆症患者群を「Mild impairment(50≦<80)」、中等度腎機能障害を有する骨粗鬆症患者群を「Moderate impairment(<50)」と表記した。また、被験薬投与群を「PTH200群」、対照薬投与群を「P群」と表記した。また、軽度腎機能障害を有する骨粗鬆症患者群と中度腎機能障害を有する骨粗鬆症患者群を併せて「Abnormal (<80)」と表記することもある。各患者はその患者のクレアチニンクリアランスをもとに上記群に分類した。具体的には、クレアチニンクリアランスが80ml/min以上を腎機能正常、50以上80未満ml/minを軽度腎機能障害、30以上50未満ml/minを中等度腎機能障害とみなした。
腎機能正常の骨粗鬆症患者群および腎機能障害(軽度・中程度)を有する骨粗鬆症患者群いずれに対しても被験薬が新規椎体骨折抑制効果を有することが明らかとなった。
腎機能正常の骨粗鬆症患者群、軽度腎機能障害を有する骨粗鬆症患者群、中等度腎機能障害を有する骨粗鬆症患者群いずれに対しても被験薬が腰椎骨密度増加効果を有することが明らかとなった。
腎機能正常の骨粗鬆症患者群、軽度腎機能障害を有する骨粗鬆症患者群、中等度腎機能障害を有する骨粗鬆症患者群いずれに対しても被験薬を投与した結果、どの群に対しても被験薬と対照薬間で有意差は認められなかった。すなわち、血清カルシウムに関する安全性において全ての群に対して被験薬は同等であることが明らかとなった。
腎機能正常の骨粗鬆症患者群、軽度腎機能障害を有する骨粗鬆症患者群、中等度腎機能障害を有する骨粗鬆症患者群それぞれに被験薬を投与した後の有害事象発現率を試験した。
腎機能正常の骨粗鬆症患者群、軽度腎機能障害を有する骨粗鬆症患者群、中等度腎機能障害を有する骨粗鬆症患者群いずれに対しても被験薬を投与した結果、どの群に対しても被験薬は対照薬の約2倍の発現率を示した。すなわち、副作用発現率に関する安全性において全ての群に対して被験薬は同等であることが明らかとなった。
被験薬投与群を「PTH200群」、対照薬投与群を「P群」と表記した。被験薬あるいは対照薬を週1回の頻度で72週間患者に投与した際の尿中カルシウム値および補正血清カルシウム値の変動について試験した結果を示す(図4~5)。
尿中カルシウム値変化率の平均値(および中央値)は、開始時に比較72週後でPTH200群3.2%(-14.7%)、P群23.6%(1.6%)で、P群に比べPTH200群で減少傾向が見られた。
補正血清カルシウム値は、両群共に平均9.3~9.6mg/dLの範囲で推移した。PTH200群の投与後の補正血清カルシウムは最小値で8.5mg/dI(48および72週後)、最大値で11.6mg/dl(4週後)であり、P群では、最小値で8.5mg/dL(4週後)、最大値で12.lmg/dI(12週後)であつた。両群共に、大きな変動は認められなかつた。
本試験で血清カルシウム上昇および低下の有害事象は認められなかった。
本試験でPTH200群はP群と比較して高Ca血症および高Ca尿症のいずれの発現も認められなかった。
Claims (26)
- カルシウム剤と併用され、かつ、1回当たり100~200単位のPTHが週1回投与されることを特徴とする、PTHを有効成分として含有する骨粗鬆症治療ないし予防剤。
- 併用されるカルシウム剤が週一回以上投与されることを特徴とする、請求項1に記載の骨粗鬆症治療ないし予防剤。
- 併用されるカルシウム剤が、カルシウムとして1日あたり200~800mg投与されることを特徴とする、請求項1または2に記載の骨粗鬆症治療ないし予防剤。
- 前記PTHがヒトPTH(1-34)である、請求項1~3のいずれかに記載の骨粗鬆症治療ないし予防剤。
- 24週または48週を超過する期間にわたり投与するための、請求項1~4いずれかに記載の骨粗鬆症治療ないし予防剤。
- 下記(1)~(3)の全ての条件を満たす骨粗鬆症患者を治療するための、請求項1~5のいずれかに記載の骨粗鬆症治療ないし予防剤;
(1)年齢が65歳以上である
(2)既存の骨折がある
(3)骨密度が若年成人平均値の80%未満である、および/または、骨萎縮度が萎縮度I度以上である。 - ステロイドを起因とする続発性骨粗鬆症、あるいは、糖尿病性骨粗鬆症を治療ないし予防するための、請求項1~6のいずれか1項に記載の骨粗鬆症治療ないし予防剤。
- 下記(1)~(8)の少なくともいずれか1の疾病を合併症として有する骨粗鬆症を治療ないし予防するための、請求項1~6のいずれか1項に記載の骨粗鬆症治療ないし予防剤;
(1)糖尿病、
(2)高血圧、
(3)高脂血症、
(4)関節痛、
(5)変形性脊椎症、
(6)変形性腰痛症、
(7)変形性股関節症、
(8)変形性顎関節症。 - 下記(1)~(6)の少なくともいずれか1つの骨粗鬆症治療薬の投与歴がある骨粗鬆症患者に投与するための、請求項1~6のいずれか1項に記載の骨粗鬆症ないし予防治療剤;
(1)L-アスパラギン酸カルシウム
(2)アルファカルシドール、
(3)エルカトニン、
(4)塩酸ラロキシフェン、
(5)メナテトレノン、
(6)乳酸カルシウム。 - 軽度腎障害または中程度腎障害を有する骨粗鬆症患者に投与するための、請求項1~6のいずれか1項に記載の骨粗鬆症治療ないし予防剤。
- 前記PTHがヒトPTH(1-34)である、請求項6~10のいずれか1項に記載の骨粗鬆症治療ないし予防剤。
- 前記PTHを有効成分として含有する骨粗鬆症治療剤が皮下注射剤である、請求項6~11のいずれかに記載の骨粗鬆症治療ないし予防剤。
- 請求項1から12のいずれか1項に記載の骨粗鬆症治療ないし予防剤と下記(1)~(6)の少なくともいずれか1つの薬剤からなる合剤または医療用キット;
(1)メトクロプラミド、
(2)ドンペリドン、
(3)ファモチジン、
(4)クエン酸モサプリド、
(5)ランソプラゾール、
(6)六神丸。 - 1回当たり100~200単位のPTHが週1回投与されることを特徴とする、PTHを有効成分として含有する骨粗鬆症治療ないし予防剤であって、下記(1)~(3)の全ての条件を満たす骨粗鬆症患者を治療するための、骨粗鬆症治療ないし予防剤;
(1)年齢が65歳以上である
(2)既存の骨折がある
(3)骨密度が若年成人平均値の80%未満である、および/または、骨萎縮度が萎縮度I度以上である。 - 1回当たり100~200単位のPTHが週1回投与されることを特徴とする、PTHを有効成分として含有する、骨折の危険性の高い骨粗鬆症治療ないし予防剤。
- 1回当たり100~200単位のPTHが週1回投与されることを特徴とする、PTHを有効成分として含有する骨粗鬆症治療ないし予防剤であって、ステロイドを起因とする続発性骨粗鬆症、あるいは、糖尿病性骨粗鬆症を治療ないし予防するための、骨粗鬆症治療ないし予防剤。
- 1回当たり100~200単位のPTHが週1回投与されることを特徴とする、PTHを有効成分として含有する骨粗鬆症治療ないし予防剤であって、軽度腎障害または中程度腎障害を有する骨粗鬆症患者に投与するための、骨粗鬆症治療ないし予防剤。
- カルシウム剤と併用され、かつ、1回当たり100~200単位のPTHが週1回投与されることを特徴とする、PTHを有効成分として含有する骨折抑制ないし予防剤。
- 併用されるカルシウム剤が週1回以上投与されることを特徴とする、請求項18に記載の骨折抑制ないし予防剤。
- 併用されるカルシウム剤が、カルシウムとして1日あたり200~800mg投与されることを特徴とする、請求項18または19に記載の骨折抑制ないし予防剤。
- 前記PTHがヒトPTH(1-34)である、請求項18~20のいずれかに記載の骨折抑制ないし予防剤。
- 下記(1)~(3)の全ての条件を満たす対象者に投与するための、請求項18~21のいずれかに記載の骨折抑制ないし予防剤;
(1)年齢が65歳以上である
(2)既存の骨折がある
(3)骨密度が若年成人平均値の80%未満である、および/または、骨萎縮度が萎縮度I度以上である。 - 前記PTHがヒトPTH(1-34)である、請求項22に記載の骨折抑制ないし予防剤。
- 前記PTHを有効成分として含有する骨折抑制ないし予防剤が皮下注射剤である、請求項22または23に記載の骨折抑制ないし予防剤。
- 骨折抑制ないし予防剤が多発骨折抑制ないし多発骨折予防剤である、請求項18~24のいずれか1項に記載の骨折抑制ないし予防剤。
- 骨折抑制ないし予防剤が増悪骨折抑制ないし増悪骨折予防剤である、請求項18~25のいずれか1項に記載の骨折抑制ないし予防剤。
Priority Applications (25)
Application Number | Priority Date | Filing Date | Title |
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EP13181715.7A EP2682125B1 (en) | 2009-09-09 | 2010-09-08 | Pth-containing therapeutic/prophylactic agent for osteoporosis, characterized in that pth is administered once a week at unit dose of 200 units |
KR20147029471A KR20140130754A (ko) | 2009-09-09 | 2010-09-08 | 1회당 100∼200 단위의 pth가 주 1회 투여되는 것을 특징으로 하는, pth 함유 골다공증 치료/예방제 |
AU2010293488A AU2010293488B2 (en) | 2009-09-09 | 2010-09-08 | PTH-containing therapeutic/prophylactic agent for osteoporosis, characterized in that PTH is administered once a week in a unit dose of 100 to 200 units |
KR1020217009475A KR102424644B1 (ko) | 2009-09-09 | 2010-09-08 | 1회당 100∼200 단위의 pth가 주 1회 투여되는 것을 특징으로 하는, pth 함유 골다공증 치료/예방제 |
RU2012108635/15A RU2564894C2 (ru) | 2009-09-09 | 2010-09-08 | Ртн-содержащий терапевтический/профилактический агент против остеопороза, характеризующийся тем, что ртн вводят один раз в неделю в стандартной дозе 100-200 единиц |
CA2772656A CA2772656A1 (en) | 2009-09-09 | 2010-09-08 | Pth-containing therapeutic/prophylactic agent for osteoporosis, characterized in that pth is administered once a week in a unit dose of 100 to 200 units |
ES10815369.3T ES2663322T3 (es) | 2009-09-09 | 2010-09-08 | Agente terapéutico/profiláctico que contiene PTH para la osteoporosis, caracterizado porque la PTH se administra una vez por semana en una dosis unitaria de 200 unidades |
KR1020207027785A KR102335703B1 (ko) | 2009-09-09 | 2010-09-08 | 1회당 100∼200 단위의 pth가 주 1회 투여되는 것을 특징으로 하는, pth 함유 골다공증 치료/예방제 |
MX2012002681A MX335951B (es) | 2009-09-09 | 2010-09-08 | Agente terapeutico/profilactico que contiene pth para la osteoporosis, caracterizado porque la pth se administra una vez a la semana en una dosis unitaria de 100 a 200 unidades. |
KR20157003153A KR20150021590A (ko) | 2009-09-09 | 2010-09-08 | 1회당 100∼200 단위의 pth가 주 1회 투여되는 것을 특징으로 하는, pth 함유 골다공증 치료/예방제 |
KR1020177019824A KR20170089018A (ko) | 2009-09-09 | 2010-09-08 | 1회당 100∼200 단위의 pth가 주 1회 투여되는 것을 특징으로 하는, pth 함유 골다공증 치료/예방제 |
IN857DEN2012 IN2012DN00857A (ja) | 2009-09-09 | 2010-09-08 | |
US13/395,000 US20120252729A1 (en) | 2009-09-09 | 2010-09-08 | Pth-containing therapeutic/prophylactic agent for osteoporosis, characterized in that pth is administered once a week in a unit dose of 100 to 200 units |
KR1020177019823A KR20170089017A (ko) | 2009-09-09 | 2010-09-08 | 1회당 100∼200 단위의 pth가 주 1회 투여되는 것을 특징으로 하는, pth 함유 골다공증 치료/예방제 |
JP2011530844A JPWO2011030774A1 (ja) | 2009-09-09 | 2010-09-08 | 1回当たり100〜200単位のpthが週1回投与されることを特徴とする、pth含有骨粗鬆症治療/予防剤 |
NZ598370A NZ598370A (en) | 2009-09-09 | 2010-09-08 | Pth-containing therapeutic/prophylactic agent for osteoporosis, characterized in that pth is administered once a week at unit dose of 100 to 200 units |
BR112012003511A BR112012003511A2 (pt) | 2009-09-09 | 2010-09-08 | agente para o tratamento ou prevenção de osteoporose, preparação de combinação ou kit de tratamento, e, agente para a inibição ou prevenção de fraturas ósseas |
EP10815369.3A EP2476429B1 (en) | 2009-09-09 | 2010-09-08 | Pth-containing therapeutic/prophylactic agent for osteoporosis, characterized in that pth is administered once a week at unit dose of 200 units |
KR1020197023161A KR20190095552A (ko) | 2009-09-09 | 2010-09-08 | 1회당 100∼200 단위의 pth가 주 1회 투여되는 것을 특징으로 하는, pth 함유 골다공증 치료/예방제 |
CN201080034494.5A CN102470164B (zh) | 2009-09-09 | 2010-09-08 | 以每周给药1次每次为100单位~200单位的pth为特征的、含有pth的骨质疏松症治疗/预防剂 |
IL217854A IL217854A (en) | 2009-09-09 | 2012-01-31 | Therapeutic / prophylactic factor containing pth for osteoporosis, characterized in that pth is given once a week in a 200 unit dose |
ZA2012/01720A ZA201201720B (en) | 2009-09-09 | 2012-03-08 | Pth-containing therapeutic/prophylactic agent for osteoporosis, characterized in that pth is administered once a week in a unit dose of 100 to 200 units |
HK12109099.7A HK1168284A1 (en) | 2009-09-09 | 2012-09-17 | Pth-containing therapeutic/prophylactic agent for osteoporosis, characterized in that pth is administered once a week at unit dose of 100 to 200 units |
US14/197,607 US20140249084A1 (en) | 2009-09-09 | 2014-03-05 | Pth-containing therapeutic/prophylactic agent for osteoporosis, characterized in that pth is administered once a week in a unit dose of 100 to 200 units |
US14/330,124 US20140357560A1 (en) | 2009-09-09 | 2014-07-14 | Pth-containing therapeutic/prophylactic agent for osteoporosis, characterized in that pth is administered once a week in a unit dose of 100 to 200 units |
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US14/197,607 Continuation US20140249084A1 (en) | 2009-09-09 | 2014-03-05 | Pth-containing therapeutic/prophylactic agent for osteoporosis, characterized in that pth is administered once a week in a unit dose of 100 to 200 units |
US14/330,124 Continuation US20140357560A1 (en) | 2009-09-09 | 2014-07-14 | Pth-containing therapeutic/prophylactic agent for osteoporosis, characterized in that pth is administered once a week in a unit dose of 100 to 200 units |
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EP (3) | EP2476429B1 (ja) |
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AU (1) | AU2010293488B2 (ja) |
BR (1) | BR112012003511A2 (ja) |
CA (1) | CA2772656A1 (ja) |
ES (3) | ES2663322T3 (ja) |
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IN (1) | IN2012DN00857A (ja) |
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