CA2698626C - A combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor - Google Patents
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Abstract
The invention relates to a combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor, said preparation being adapted for (a) the administration of parathyroid hormone during a period of approximately 6 to 24 months; (b) after the administration of parathyroid hormone has been terminated, the administration of a bone resorption inhibitor during a period of approximately 12 to 36 months.
Description
PHARMACEUTICAL USE
TECHNICAL FIELD
A COMBINED PHARMACEU'I7CAL PREPARATiON COMPRISING PARATHYROID HORMONE AND A
BONE
RFSORPT[ON INHIBITOR
BACKGROUND ART
Bone formation and resorption In the adult individual (males as well as females) bone is continuously subject to remodeling. This is a process where bone resorption is closely linked to bone formation, through the concerted action of the bone active cells, i.e. the bone forming osteoblasts and the bone resorbing osteoclasts. These cells together form what is called a basal multicellular (metabolic) unit, or BMU. The remodeling process starts with activation of the lining cells (the cells that cover the unmineralized bone). The lining cells resorb the unmineralized bone, then retract and leave room for the osteoclasts which resorb the old, mineralized bone and create an environment which attracts the osteoblast to the same site.
The osteoblasts thereafter lay down the organic matrix, which subsequently is becoming mineralized to form new bone. The resulting bone mass is thus determined by the balance between resorption by osteoclasts and formation by osteoblasts.
Consequently, there is a close relationship between the actions of the two cell types which is referred to as "coupling"; bone resorption always precedes bone formation.
The coupling phenomenon means that even when the intention is to produce a positive balance per cycle it is still necessary to start with bone resorption. Typically, a BMU cycle takes 3 to 6 months to complete.
= WO 98/57656 PCT/SE98/01095
TECHNICAL FIELD
A COMBINED PHARMACEU'I7CAL PREPARATiON COMPRISING PARATHYROID HORMONE AND A
BONE
RFSORPT[ON INHIBITOR
BACKGROUND ART
Bone formation and resorption In the adult individual (males as well as females) bone is continuously subject to remodeling. This is a process where bone resorption is closely linked to bone formation, through the concerted action of the bone active cells, i.e. the bone forming osteoblasts and the bone resorbing osteoclasts. These cells together form what is called a basal multicellular (metabolic) unit, or BMU. The remodeling process starts with activation of the lining cells (the cells that cover the unmineralized bone). The lining cells resorb the unmineralized bone, then retract and leave room for the osteoclasts which resorb the old, mineralized bone and create an environment which attracts the osteoblast to the same site.
The osteoblasts thereafter lay down the organic matrix, which subsequently is becoming mineralized to form new bone. The resulting bone mass is thus determined by the balance between resorption by osteoclasts and formation by osteoblasts.
Consequently, there is a close relationship between the actions of the two cell types which is referred to as "coupling"; bone resorption always precedes bone formation.
The coupling phenomenon means that even when the intention is to produce a positive balance per cycle it is still necessary to start with bone resorption. Typically, a BMU cycle takes 3 to 6 months to complete.
= WO 98/57656 PCT/SE98/01095
2 The rate by which the basal metabolic (multicellular) units are being activated, the activation frequency, also plays a role. A high activation frequency increases the rate by which bone is being lost if there is a negative balance per remodeling cycle.
When activation frequency is increased the space that is being occupied by remodeling, the remodeling space, is also increased. This will give a lowered bone mass, since a greater portion of the bone is subject to resorption as part of the remodeling process.
The above outlined sequence of events is well known in the art and has formed the basis for the understanding of metabolic bone diseases and possible ways for their treatments.
Osteoporosis is a disease which is characterized by a reduced amount of bone tissue, usually of normal composition, which has reduced strength due to a combination of low bone mass and impaired architecture, and therefore carries an increased risk of fractures. In terms of remodeling, osteoporosis is the result of negative bone balance per remodeling cycle, i.e. less bone is formed than is being resorbed. In a small proportion of patients it is possible to determine a specific disease as responsible for the loss of bone (e.g.
malabsorption of calcium and hypersecretion of corticosteroid hormones) but in the majority of patients no such disorder is identified. Such patients are classified as having "primary" osteoporosis. Bone is lost with advancing age in both sexes, but in females there zo is generally an increased rate of loss during the first years after the menopause (hence the term "postmenopausal" osteoporosis).
Bone resorption inhibitors A number of agents have been used for the prevention and treatment of bone loss and osteoporosis, e.g. estrogen, vitamin D and bisphosphonates, such as alendronate (for a review, see: Osteoporosis (Marcus, R., Feldman, D. and Kelsey, F., Eds.) Academic Press, San Diego, 1996). Such agents mainly act through inhibition of bone resorption. By reducing the resorbed amount in each remodeling cycle, while keeping the formation intact, it is possible to reduce the negative bone balance and retard bone loss. At the same time
When activation frequency is increased the space that is being occupied by remodeling, the remodeling space, is also increased. This will give a lowered bone mass, since a greater portion of the bone is subject to resorption as part of the remodeling process.
The above outlined sequence of events is well known in the art and has formed the basis for the understanding of metabolic bone diseases and possible ways for their treatments.
Osteoporosis is a disease which is characterized by a reduced amount of bone tissue, usually of normal composition, which has reduced strength due to a combination of low bone mass and impaired architecture, and therefore carries an increased risk of fractures. In terms of remodeling, osteoporosis is the result of negative bone balance per remodeling cycle, i.e. less bone is formed than is being resorbed. In a small proportion of patients it is possible to determine a specific disease as responsible for the loss of bone (e.g.
malabsorption of calcium and hypersecretion of corticosteroid hormones) but in the majority of patients no such disorder is identified. Such patients are classified as having "primary" osteoporosis. Bone is lost with advancing age in both sexes, but in females there zo is generally an increased rate of loss during the first years after the menopause (hence the term "postmenopausal" osteoporosis).
Bone resorption inhibitors A number of agents have been used for the prevention and treatment of bone loss and osteoporosis, e.g. estrogen, vitamin D and bisphosphonates, such as alendronate (for a review, see: Osteoporosis (Marcus, R., Feldman, D. and Kelsey, F., Eds.) Academic Press, San Diego, 1996). Such agents mainly act through inhibition of bone resorption. By reducing the resorbed amount in each remodeling cycle, while keeping the formation intact, it is possible to reduce the negative bone balance and retard bone loss. At the same time
3 they reduce the activation frequency and since the remodeling space is reduced there is only a limited increase of bone mass.
Most studies with bisphosphonates indicate that they increase bone mineral density of the lumbar spine in the actively treated patients with around I to 5%, depending on dose and type of bisphosphonate, during the first year of treatment, when compared with controi patients given placebo. Both patients and controls generally receive calcium supplementation to ensure adequate calcium nutrition.
The antiresorptive agents can retard bone loss but, by definition, they do not increase bone mass within each remodeling unit. Many patients with fractures have severe bone loss at the time they come to clinical attention. Inhibition of bone resorption might not be enough to prevent fracture recurrences. Therefore it is urgent to develop therapies that can increase bone mass, i.e. anabolic agents.
Parathyroid hormone Parathyroid hormone (PTH) is an 84 amino acid polypeptide which is normally secreted from the parathyroid glands. PTH has an important physiological role to maintain serum calcium within a narrow range. Furthermore, it has anabolic properties when given intermittently. This has been well documented in a number of animal and open clinical studies, recently reviewed by Dempster, D.W. et al. (Endocrine Reviews 1993, vol. 14, 690-709). PTH has a multitude of effects on bone. Part of it is through the remodeling cycle. PTH causes both increased activation frequency and a positive balance per cycle.
Human PTH may be obtained through peptide synthesis or from genetically engineered yeast, bacterial or mammalian cell hosts. Synthetic human PTH is commercially available from Bachem Inc., Bubendorf, Switzerland. Production of recombinant human parathyroid hormone is disclosed in e.g. EP-B-038375 1.
Most studies with bisphosphonates indicate that they increase bone mineral density of the lumbar spine in the actively treated patients with around I to 5%, depending on dose and type of bisphosphonate, during the first year of treatment, when compared with controi patients given placebo. Both patients and controls generally receive calcium supplementation to ensure adequate calcium nutrition.
The antiresorptive agents can retard bone loss but, by definition, they do not increase bone mass within each remodeling unit. Many patients with fractures have severe bone loss at the time they come to clinical attention. Inhibition of bone resorption might not be enough to prevent fracture recurrences. Therefore it is urgent to develop therapies that can increase bone mass, i.e. anabolic agents.
Parathyroid hormone Parathyroid hormone (PTH) is an 84 amino acid polypeptide which is normally secreted from the parathyroid glands. PTH has an important physiological role to maintain serum calcium within a narrow range. Furthermore, it has anabolic properties when given intermittently. This has been well documented in a number of animal and open clinical studies, recently reviewed by Dempster, D.W. et al. (Endocrine Reviews 1993, vol. 14, 690-709). PTH has a multitude of effects on bone. Part of it is through the remodeling cycle. PTH causes both increased activation frequency and a positive balance per cycle.
Human PTH may be obtained through peptide synthesis or from genetically engineered yeast, bacterial or mammalian cell hosts. Synthetic human PTH is commercially available from Bachem Inc., Bubendorf, Switzerland. Production of recombinant human parathyroid hormone is disclosed in e.g. EP-B-038375 1.
4 PTH when given alone, to a patient with osteoporosis, will stimulate bone formation within each remodeling cycle and cause a positive bone balance within each cycle. At the same time the number of remodeling units will greatly increase, i.e. the activation frequency is enhanced. These two mechanisms act in different directions on bone mass.
During therapy with PTH it has been calculated that the activation frequency is doubled.
Although this will mean that the remodeling space is increased, bone mass (or bone density) is increased in trabecular bone. Thus bone mineral density is increased by 5 to 10% per year in the lumbar spine and is largely unaffected in the femoral neck, which io contains a higher proportion of cortical bone. These two sites are where the most common and clinically important fractures occur in the population, both in males and females.
The presently known methods for treatment of osteoporosis utilize bone resorption inhibition of the BMU cycle, but have the drawbacks that their onset of effect is slow and limited, and that they only cause moderate increases of bone mineral density (bone mass) and may therefore be insufficient for the treatment of patients with osteoporosis in a stage where there is high risk of recurrent fractures. Furthermore, it has not been shown that present methods can improve on the altered architecture that is a hallmark of advanced osteoporosis.
A method of treatment of bone metabolism disorders, utilizing the order of events in the BMU cycle, and comprising administering a bone active phosphonate and, sequentially, parathyroid hormone, is disclosed in WO 96/07417 (The Procter & Gamble Company). In that method, the bone active phosphonate is given for a period of greater than about 6 months, in various dosage regimens, but always prior to PTH.
Hodsman, A. et al. (J. Bone and Mineral Research, Vol. 10, Suppl. 1, abstract No. P288, p.
S200, 1995) discloses a clinical trial involving treatment with PTH for 28 days, with our without sequential calcitonin for 42 days, with this cycle repeated at 3 months intervals for 2 years. Patients were then crossed over to clodronate, 28 days per 3 months, for one year.
WO 98/57656 P("T/SE98/01095 However, there was no beneficial effect in bone density from this sequential PTH/bisphosphonate treatment regimen.
WO 97/31640 (publication date 4 September 1997) discloses a pharmaceutical s composition comprising (a) an estrogen agonist/antagonist; and (b) a bone activating compound, such as parathyroid hormone. However, the periods of treatment are broadly defined and it is stated that the said compounds can be administered for periods from about three months to about three years.
DISCLOSURE OF THE INVENTION
Different combinations are conceivable for treating osteoporosis with resorption inhibitors and anabolic agents. The starting point for treatment, i.e. when the patient comes to the is attention of the clinic, is a decreasing BMD (bone mineral density), due to the net formation rate being below the net resorption rate. Initial administration of a resorption inhibitor will reduce resorption rate by reducing the remodeling space and the activation frequency. Subsequent administration of an anabolic agent will then increase activation frequency and create an increased remodeling space. This coupling between resorption and reformation allows the formation rate to increase above the resorption rate and lead to increases in BMD. The resorption activity is a prerequisite for subsequent bone formation within the BMU.
However, it has surprisingly been found that when the anabolic agent was administered initially, i.e. as the starting point, and is then followed by administration of the resorption inhibitor, the total increase in BMD is not only maintained but also much further increased.
It appears that the initial increase in activation frequency by the anabolic agent creates not only formation of new bone, but also a large remodeling space. Subsequent administration by the resorption inhibitor, inhibits further increases in the remodeling space, by decreasing the activation frequency. Upon closing, or diminishing, the existing remodeling space, .WO 98/57656 PCT/SE98/01095 BMD is then allowed to increase more than was achieved during treatment with the anabolic agent alone during the first period.
The present invention is thus based on the concept of remodeling. By overriding the resorptive phase of the BMU over several consecutive cycles, it fortifies the anabolic action of PTH. In addition, by prolonging the treatment over several BMU cycles, it takes advantage of the opposite influences on the activation frequency which is increased by PTH and later reduced by bisphosphonates.
As mentioned above, WO 96/07417 discloses a method of treatment of bone metabolism disorders, comprising administering a bone active phosphonate and, subsequently, parathyroid hormone. The bone active phosphonate was thus given prior to PTH.
The order of treatment regimens provides principally different treatment responses.
Slowing down the remodeling cycle with a resorption inhibitor would linlit the maximum anabolic effect that can be obtained with PTH. On the other hand, if PTH is given first over several BMU
cycles, not only will it enhance the BMU positive bone balance significantly, it will also increase activation frequency to such an extent that effects of subsequent antiresorptive therapy will be enhanced.
According to the present invention, a bisphosphonate is given after PTH
treatment, in order not only to maintain bone mass on the higher level by its antiresorptive action, but also to increase BMD by filling in the increased remodeling space through the reduction of activation frequency.
A BMU cycle, involving activation, resorption, formation, typically takes 3 to 6 months to complete. The number of BMU cycles acting concurrently determines the remodeling space. In order to create an increased and sustained remodeling space, treatment with an agent that increases the activation frequency must be of sufficient duration, i.e. it must cover several BMU cycles (e.g. 6 to 12 months). Only then can the full potential of the treatment, with regards to increases in BMD, develop.
' WO 98/57656 PCT/SE98/01095 It has thus surprisingly been found that the method of treatment according to the invention achieves the advantageous result that bone mass is first rapidly increased during PTH
treatment and thereafter further bone mineral density is gained, compared to the results achieved with bisphosphonates alone without prior activation by PTH. These findings are in contrast to previous studies in humans.
Consequently, the present invention provides in a first aspect a combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor, said preparation being adapted for (a) the administration of parathyroid hormone during a io period of approximately 6 to 24 months, preferably about 12 (or above 12) months to 24 months or about 12 (or above 12) months to 18 months, or more preferably about months; and (b) after the administration of said parathyroid hormone has been terminated, the administration of a bone resorption inhibitor during a period of approximately 6 to 36 months, preferably about 12 to 36 months or about 12 to 18 months, or more preferably 1s about 12 months.
This sequence of treatments can be repeated at intervals of one to five years, until BMD
has reached a value corresponding to "young normal mean". Preferably, the interval between treatments coincides with the period of one treatment cycle, i.e. 12 to 60 months, 20 preferably 24 to 60 months or 24 to 42 months, or more preferably 30 to 36 months.
The term "parathyroid hormone" (PTH) encompasses naturally occurring human PTH, as well as synthetic or recombinant PTH (rPTH).
25 Further, the term "parathyroid hormone" encompasses full-length PTH(1-84) as well as PTH fragments. It will thus be understood that fragments of PTH variants, in amounts giving equivalent biological activity to PTH(1-84), can be incorporated in the formulations according to the invention, if desired. Fragments of PTH incorporate at least the amino acid residues of PTH necessary for a biological activity similar to that of intact PTH. Examples 30 of such fragments are PTH(1-31), PTH(1-34), PTH(1-36), PTH(1-37), PTH(1-38), PTH(1-41), PTH(28-48) and PTH(25-39).
The term "parathyroid hormone" also encompasses variants and functional analogues of PTH. The present invention thus includes pharmaceutical formulations comprising such PTH variants and functional analogues, carrying modifications like substitutions, deletions, insertions, inversions or cyclisations, but nevertheless having substantially the biological activities of parathyroid hormone. Stability-enhanced variants of PTH are known in the art from e.g. WO 92/11286 and WO 93/20203. Variants of PTH can e.g. incorporate amino acid substitutions that improve PTH stability and half-life, such as the replacement of methionine residues at positions 8 and/or 18, and replacement of asparagine at position 16.
to Cyclized PTH analogues are disclosed in e.g. WO 98/05683.
Consequently, the invention includes a preparation as described above wherein the said parathyroid hormone is selected from the group consisting of:
(a) full-length parathyroid hormone;
1s (b) biologically active variants of full-length parathyroid hormone;
(c) biologically active parathyroid hormone fragments; and (d) biologically active variants of parathyroid hormone fragments.
In this context, the term "biologically active" should be understood as eliciting a sufficient response in a bioassay for PTH activity, such as the rat osteosarcoma cell-based assay for 20 PTH-stimulated adenylate cyclase production (see Rodan et al. (1983) J.
Clin. Invest. 72, 1511; and Rabbani et al. (1988) Endocrinol. 123, 2709).
The PTH to be used in the pharmaceutical preparation according to the invention is preferably recombinant human PTH, such as full-length recombinant human PTH.
25 Parathyroid hormone can be subcutaneously administered in an amount of approximately 0.1 to 5 g/kg body weight, preferably 0.5 to 3 g/kg, or more preferably 1 to 2.5 g/kg body weight. Orally, nasally or pulmonary, PTH can be administered in an amount of 0.1 g to 15 mg/kg.
30 The said bone resorption inhibitor can be a bisphosphonate, e.g.
alendronate; or a substance with estrogen-like effect, e.g. estrogen; or a selective estrogen receptor modulator, e.g.
raloxifene, tamoxifene, droloxifene, toremifene, idoxifene, or levormeloxifene; or a calcitonin-like substance, e.g. calcitonin; or a vitamin D analog; or a calcium salt.
The said bone resorption inhibitor is preferably administered in an amount of 0.05 to 500 mg, preferably around 10 mg.
In a further aspect, the invention provides the use of parathyroid hormone in combination with a bone resorption inhibitor in the manufacture of a medicament for the treatment or prevention of bone-related diseases, in particular osteoporosis, said medicament being adapted for (a) the administration of parathyroid hormone during a period of approximately 6 to 24 months; (b) after the administration of parathyroid hormone has been terminated, the administration of a bone resorption inhibitor during a period of approximately 12 to 36 months. The parathyroid hormone and the bone resorption inhibitor are as defined above.
In yet a further aspect, the invention provides a method of treatment or prevention of bone-related diseases, in particular osteoporosis, which comprises administering to a mammal, including man, in need of such treatment an effective amount of a pharmaceutical preparation as defined in the above. Consequently, such a method comprises administering to a mammal, including man, in need of such treatment (a) an effective amount of parathyroid hormone during a period of approximately 6 to 24 months; and (b) after the administration of parathyroid hormone has been terminated, an effective amount of a bone resorption inhibitor during a period of approximately 12 to 36 months.
The invention also includes a method of treatment or prevention of bone-related diseases which comprises administering, to a patient who has already been subject to treatment with parathyroid hormone during a period of approximately 6 to 24 months, after the administration of parathyroid hormone has been terminated, an effective amount of a bone resorption inhibitor during a period of approximately 12 to 36 months.
EXAMPLE OF THE INVENTION
Postmenopausal females (n=172) with osteoporosis were given intact human PTH
(1-84), as a subcutaneous injection, for one year in doses from 50 to 100 micrograms daily. It was shown that bone mineral density of the spine was increased in the lumbar spine, on the average by 8%. Increases in individual patients were considerably more than 10%. The
During therapy with PTH it has been calculated that the activation frequency is doubled.
Although this will mean that the remodeling space is increased, bone mass (or bone density) is increased in trabecular bone. Thus bone mineral density is increased by 5 to 10% per year in the lumbar spine and is largely unaffected in the femoral neck, which io contains a higher proportion of cortical bone. These two sites are where the most common and clinically important fractures occur in the population, both in males and females.
The presently known methods for treatment of osteoporosis utilize bone resorption inhibition of the BMU cycle, but have the drawbacks that their onset of effect is slow and limited, and that they only cause moderate increases of bone mineral density (bone mass) and may therefore be insufficient for the treatment of patients with osteoporosis in a stage where there is high risk of recurrent fractures. Furthermore, it has not been shown that present methods can improve on the altered architecture that is a hallmark of advanced osteoporosis.
A method of treatment of bone metabolism disorders, utilizing the order of events in the BMU cycle, and comprising administering a bone active phosphonate and, sequentially, parathyroid hormone, is disclosed in WO 96/07417 (The Procter & Gamble Company). In that method, the bone active phosphonate is given for a period of greater than about 6 months, in various dosage regimens, but always prior to PTH.
Hodsman, A. et al. (J. Bone and Mineral Research, Vol. 10, Suppl. 1, abstract No. P288, p.
S200, 1995) discloses a clinical trial involving treatment with PTH for 28 days, with our without sequential calcitonin for 42 days, with this cycle repeated at 3 months intervals for 2 years. Patients were then crossed over to clodronate, 28 days per 3 months, for one year.
WO 98/57656 P("T/SE98/01095 However, there was no beneficial effect in bone density from this sequential PTH/bisphosphonate treatment regimen.
WO 97/31640 (publication date 4 September 1997) discloses a pharmaceutical s composition comprising (a) an estrogen agonist/antagonist; and (b) a bone activating compound, such as parathyroid hormone. However, the periods of treatment are broadly defined and it is stated that the said compounds can be administered for periods from about three months to about three years.
DISCLOSURE OF THE INVENTION
Different combinations are conceivable for treating osteoporosis with resorption inhibitors and anabolic agents. The starting point for treatment, i.e. when the patient comes to the is attention of the clinic, is a decreasing BMD (bone mineral density), due to the net formation rate being below the net resorption rate. Initial administration of a resorption inhibitor will reduce resorption rate by reducing the remodeling space and the activation frequency. Subsequent administration of an anabolic agent will then increase activation frequency and create an increased remodeling space. This coupling between resorption and reformation allows the formation rate to increase above the resorption rate and lead to increases in BMD. The resorption activity is a prerequisite for subsequent bone formation within the BMU.
However, it has surprisingly been found that when the anabolic agent was administered initially, i.e. as the starting point, and is then followed by administration of the resorption inhibitor, the total increase in BMD is not only maintained but also much further increased.
It appears that the initial increase in activation frequency by the anabolic agent creates not only formation of new bone, but also a large remodeling space. Subsequent administration by the resorption inhibitor, inhibits further increases in the remodeling space, by decreasing the activation frequency. Upon closing, or diminishing, the existing remodeling space, .WO 98/57656 PCT/SE98/01095 BMD is then allowed to increase more than was achieved during treatment with the anabolic agent alone during the first period.
The present invention is thus based on the concept of remodeling. By overriding the resorptive phase of the BMU over several consecutive cycles, it fortifies the anabolic action of PTH. In addition, by prolonging the treatment over several BMU cycles, it takes advantage of the opposite influences on the activation frequency which is increased by PTH and later reduced by bisphosphonates.
As mentioned above, WO 96/07417 discloses a method of treatment of bone metabolism disorders, comprising administering a bone active phosphonate and, subsequently, parathyroid hormone. The bone active phosphonate was thus given prior to PTH.
The order of treatment regimens provides principally different treatment responses.
Slowing down the remodeling cycle with a resorption inhibitor would linlit the maximum anabolic effect that can be obtained with PTH. On the other hand, if PTH is given first over several BMU
cycles, not only will it enhance the BMU positive bone balance significantly, it will also increase activation frequency to such an extent that effects of subsequent antiresorptive therapy will be enhanced.
According to the present invention, a bisphosphonate is given after PTH
treatment, in order not only to maintain bone mass on the higher level by its antiresorptive action, but also to increase BMD by filling in the increased remodeling space through the reduction of activation frequency.
A BMU cycle, involving activation, resorption, formation, typically takes 3 to 6 months to complete. The number of BMU cycles acting concurrently determines the remodeling space. In order to create an increased and sustained remodeling space, treatment with an agent that increases the activation frequency must be of sufficient duration, i.e. it must cover several BMU cycles (e.g. 6 to 12 months). Only then can the full potential of the treatment, with regards to increases in BMD, develop.
' WO 98/57656 PCT/SE98/01095 It has thus surprisingly been found that the method of treatment according to the invention achieves the advantageous result that bone mass is first rapidly increased during PTH
treatment and thereafter further bone mineral density is gained, compared to the results achieved with bisphosphonates alone without prior activation by PTH. These findings are in contrast to previous studies in humans.
Consequently, the present invention provides in a first aspect a combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor, said preparation being adapted for (a) the administration of parathyroid hormone during a io period of approximately 6 to 24 months, preferably about 12 (or above 12) months to 24 months or about 12 (or above 12) months to 18 months, or more preferably about months; and (b) after the administration of said parathyroid hormone has been terminated, the administration of a bone resorption inhibitor during a period of approximately 6 to 36 months, preferably about 12 to 36 months or about 12 to 18 months, or more preferably 1s about 12 months.
This sequence of treatments can be repeated at intervals of one to five years, until BMD
has reached a value corresponding to "young normal mean". Preferably, the interval between treatments coincides with the period of one treatment cycle, i.e. 12 to 60 months, 20 preferably 24 to 60 months or 24 to 42 months, or more preferably 30 to 36 months.
The term "parathyroid hormone" (PTH) encompasses naturally occurring human PTH, as well as synthetic or recombinant PTH (rPTH).
25 Further, the term "parathyroid hormone" encompasses full-length PTH(1-84) as well as PTH fragments. It will thus be understood that fragments of PTH variants, in amounts giving equivalent biological activity to PTH(1-84), can be incorporated in the formulations according to the invention, if desired. Fragments of PTH incorporate at least the amino acid residues of PTH necessary for a biological activity similar to that of intact PTH. Examples 30 of such fragments are PTH(1-31), PTH(1-34), PTH(1-36), PTH(1-37), PTH(1-38), PTH(1-41), PTH(28-48) and PTH(25-39).
The term "parathyroid hormone" also encompasses variants and functional analogues of PTH. The present invention thus includes pharmaceutical formulations comprising such PTH variants and functional analogues, carrying modifications like substitutions, deletions, insertions, inversions or cyclisations, but nevertheless having substantially the biological activities of parathyroid hormone. Stability-enhanced variants of PTH are known in the art from e.g. WO 92/11286 and WO 93/20203. Variants of PTH can e.g. incorporate amino acid substitutions that improve PTH stability and half-life, such as the replacement of methionine residues at positions 8 and/or 18, and replacement of asparagine at position 16.
to Cyclized PTH analogues are disclosed in e.g. WO 98/05683.
Consequently, the invention includes a preparation as described above wherein the said parathyroid hormone is selected from the group consisting of:
(a) full-length parathyroid hormone;
1s (b) biologically active variants of full-length parathyroid hormone;
(c) biologically active parathyroid hormone fragments; and (d) biologically active variants of parathyroid hormone fragments.
In this context, the term "biologically active" should be understood as eliciting a sufficient response in a bioassay for PTH activity, such as the rat osteosarcoma cell-based assay for 20 PTH-stimulated adenylate cyclase production (see Rodan et al. (1983) J.
Clin. Invest. 72, 1511; and Rabbani et al. (1988) Endocrinol. 123, 2709).
The PTH to be used in the pharmaceutical preparation according to the invention is preferably recombinant human PTH, such as full-length recombinant human PTH.
25 Parathyroid hormone can be subcutaneously administered in an amount of approximately 0.1 to 5 g/kg body weight, preferably 0.5 to 3 g/kg, or more preferably 1 to 2.5 g/kg body weight. Orally, nasally or pulmonary, PTH can be administered in an amount of 0.1 g to 15 mg/kg.
30 The said bone resorption inhibitor can be a bisphosphonate, e.g.
alendronate; or a substance with estrogen-like effect, e.g. estrogen; or a selective estrogen receptor modulator, e.g.
raloxifene, tamoxifene, droloxifene, toremifene, idoxifene, or levormeloxifene; or a calcitonin-like substance, e.g. calcitonin; or a vitamin D analog; or a calcium salt.
The said bone resorption inhibitor is preferably administered in an amount of 0.05 to 500 mg, preferably around 10 mg.
In a further aspect, the invention provides the use of parathyroid hormone in combination with a bone resorption inhibitor in the manufacture of a medicament for the treatment or prevention of bone-related diseases, in particular osteoporosis, said medicament being adapted for (a) the administration of parathyroid hormone during a period of approximately 6 to 24 months; (b) after the administration of parathyroid hormone has been terminated, the administration of a bone resorption inhibitor during a period of approximately 12 to 36 months. The parathyroid hormone and the bone resorption inhibitor are as defined above.
In yet a further aspect, the invention provides a method of treatment or prevention of bone-related diseases, in particular osteoporosis, which comprises administering to a mammal, including man, in need of such treatment an effective amount of a pharmaceutical preparation as defined in the above. Consequently, such a method comprises administering to a mammal, including man, in need of such treatment (a) an effective amount of parathyroid hormone during a period of approximately 6 to 24 months; and (b) after the administration of parathyroid hormone has been terminated, an effective amount of a bone resorption inhibitor during a period of approximately 12 to 36 months.
The invention also includes a method of treatment or prevention of bone-related diseases which comprises administering, to a patient who has already been subject to treatment with parathyroid hormone during a period of approximately 6 to 24 months, after the administration of parathyroid hormone has been terminated, an effective amount of a bone resorption inhibitor during a period of approximately 12 to 36 months.
EXAMPLE OF THE INVENTION
Postmenopausal females (n=172) with osteoporosis were given intact human PTH
(1-84), as a subcutaneous injection, for one year in doses from 50 to 100 micrograms daily. It was shown that bone mineral density of the spine was increased in the lumbar spine, on the average by 8%. Increases in individual patients were considerably more than 10%. The
5 changes of the femoral neck were smaller and ranged from 1 to 3 %.
When administration of PTH was interrupted, some patients (approximately 60) were given the bisphosphonate alendronate in a standard dose of 10 mg for one year. After the combined treatment, bone mineral density was further increased in that group of patients.
10 The average gain in the femoral neck over the two years was 6% and of the lumbar spine 15%. Again, some individual responses were considerably larger and amounted to more than 25% in the spine.
These new observations demonstrate that it is possible to achieve an enhanced effect on bone mineral density with the sequential administration of PTH and bisphosphonates.
When administration of PTH was interrupted, some patients (approximately 60) were given the bisphosphonate alendronate in a standard dose of 10 mg for one year. After the combined treatment, bone mineral density was further increased in that group of patients.
10 The average gain in the femoral neck over the two years was 6% and of the lumbar spine 15%. Again, some individual responses were considerably larger and amounted to more than 25% in the spine.
These new observations demonstrate that it is possible to achieve an enhanced effect on bone mineral density with the sequential administration of PTH and bisphosphonates.
Claims (156)
1. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 50 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1 -84) is in a post-menopausal female.
2. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 51 jig for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
3. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 52 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
4. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 53 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
5. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 54 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
6. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 55 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
7. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 56 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
8. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 57 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
9. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 58 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
10. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 59 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
11. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 60 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
12. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 61 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
13. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 62 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
14. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 63 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
15. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 64 Kg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
16. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 65 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
17. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 66 Kg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
18. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 67 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
19. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 68 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
20. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 69 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
21. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 70 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
22. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 71 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
23. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 72 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
24. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 73 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
25. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 74 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
26. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 75 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
27. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 76 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
28. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 77 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
29. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 78 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
30. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 79 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
31. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 80 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
32. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 81 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
33. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 82 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
34. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 83 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
35. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 84 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
36. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 85 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
37. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 86 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
38. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 87 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
39. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 88 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
40. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 89 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
41. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 90 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
42. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 91 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
43. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 92 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
44. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 93 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
45. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 94 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
46. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 95 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
47. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 96 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
48. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 97 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
49. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 98 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
50. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 99 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
51. Use of human parathyroid hormone (1-84) (PTH(1-84)) in the manufacture of a medicament for the treatment of osteoporosis, wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form comprising about 100 µg for one year, wherein PTH(1-84) is the only therapeutically active compound in the medicament and wherein the use of the PTH(1-84) is in a post-menopausal female.
52. The use according to any one of claims 1 to 51, wherein the bone mineral density of the lumbar spine is increased by about 8%.
53. A pharmaceutical kit comprising about 50 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
54. A pharmaceutical kit comprising about 51 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
55. A pharmaceutical kit comprising about 52 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
56. A pharmaceutical kit comprising about 53 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
57. A pharmaceutical kit comprising about 54 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
58. A pharmaceutical kit comprising about 55 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
59. A pharmaceutical kit comprising about 56 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
60. A pharmaceutical kit comprising about 57 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
61. A pharmaceutical kit comprising about 58 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
62. A pharmaceutical kit comprising about 59 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
63. A pharmaceutical kit comprising about 60 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
64. A pharmaceutical kit comprising about 61 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
65. A pharmaceutical kit comprising about 62 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
66. A pharmaceutical kit comprising about 63 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
67. A pharmaceutical kit comprising about 64µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
68. A pharmaceutical kit comprising about 65 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
69. A pharmaceutical kit comprising about 66 pig of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
70. A pharmaceutical kit comprising about 67 1..tg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
71. A pharmaceutical kit comprising about 68 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
72. A pharmaceutical kit comprising about 69 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
73. A pharmaceutical kit comprising about 70 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
74. A pharmaceutical kit comprising about 71 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
75. A pharmaceutical kit comprising about 72 pg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
76. A pharmaceutical kit comprising about 73 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
77. A pharmaceutical kit comprising about 74 1.tg of human parathyroid hormone (1-84) (PT11(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
78. A pharmaceutical kit comprising about 75 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
79. A pharmaceutical kit comprising about 76 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
80. A pharmaceutical kit comprising about 77 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
81. A pharmaceutical kit comprising about 78 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
82. A pharmaceutical kit comprising about 79 pig of human parathyroid hormone (1-84) (P111(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
83. A pharmaceutical kit comprising about 80 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
84. A pharmaceutical kit comprising about 81 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
85. A pharmaceutical kit comprising about 82 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
86. A pharmaceutical kit comprising about 83 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
87. A pharmaceutical kit comprising about 84 pig of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
88. A pharmaceutical kit comprising about 85 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
89. A pharmaceutical kit comprising about 86 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
90. A pharmaceutical kit comprising about 87 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
91. A pharmaceutical kit comprising about 88 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
92. A pharmaceutical kit comprising about 89 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
93. A pharmaceutical kit comprising about 90 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
94. A pharmaceutical kit comprising about 91 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
95. A pharmaceutical kit comprising about 92 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
96. A pharmaceutical kit comprising about 93 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
97. A pharmaceutical kit comprising about 94 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
98. A pharmaceutical kit comprising about 95 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
99. A pharmaceutical kit comprising about 96 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
100. A pharmaceutical kit comprising about 97 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
101. A pharmaceutical kit comprising about 98 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
102. A pharmaceutical kit comprising about 99 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
103. A pharmaceutical kit comprising about 100 µg of human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) daily for one year to a post-menopausal female.
104. The kit according to any one of claims 53 to 103, wherein administration of the PTH(1-84) daily for one year to a post-menopausal female increases the bone mineral density of the lumbar spine by about 8%.
105. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 50 µg for one year to a post-menopausal female.
106. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 51 µg for one year to a post-menopausal female.
107. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 52 µg for one year to a post-menopausal female.
108. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 53 µg for one year to a post-menopausal female.
109. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 54 µg for one year to a post-menopausal female.
110. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 55 µg for one year to a post-menopausal female.
111. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 56 µg for one year to a post-menopausal female.
112. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 57 pig for one year to a post-menopausal female.
113. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 58 µg for one year to a post-menopausal female.
114. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 59 µg for one year to a post-menopausal female.
115. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 60 µg for one year to a post-menopausal female.
116. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 61 µg for one year to a post-menopausal female.
117. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 62 µg for one year to a post-menopausal female.
118. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 63 µg for one year to a post-menopausal female.
119. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 64 µg for one year to a post-menopausal female.
120. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 65 µg for one year to a post-menopausal female.
121. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 66 µg for one year to a post-menopausal female.
122. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 67 µg for one year to a post-menopausal female.
123. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 68 µg for one year to a post-menopausal female.
124. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 69 µg for one year to a post-menopausal female.
125. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 70 µg for one year to a post-menopausal female.
126. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 71 µg for one year to a post-menopausal female.
127. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 72 µg for one year to a post-menopausal female.
128. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 73 µg for one year to a post-menopausal female.
129. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 74 µg for one year to a post-menopausal female.
130. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1 -84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 75 µg for one year to a post-menopausal female.
131. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1 -84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 76 µg for one year to a post-menopausal female.
132. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 77 µg for one year to a post-menopausal female.
133. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 78 µg for one year to a post-menopausal female.
134. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 79 µg for one year to a post-menopausal female.
135. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 80 µg for one year to a post-menopausal female.
136. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 81 µg for one year to a post-menopausal female.
137. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 82 µg for one year to a post-menopausal female.
138. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 83 µg for one year to a post-menopausal female.
139. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of' about 84 µg for one year to a post-menopausal female.
140. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 85 µg for one year to a post-menopausal female.
141. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 86 µg for one year to a post-menopausal female.
142. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 87 µg for one year to a post-menopausal female.
143. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 88 µg for one year to a post-menopausal female.
144. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the P1H(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 89 µg for one year to a post-menopausal female.
145. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 90 µg for one year to a post-menopausal female.
146. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 91 µg for one year to a post-menopausal female.
147. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 92 µg for one year to a post-menopausal female.
148. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 93 µg for one year to a post-menopausal female.
149. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 94 µg for one year to a post-menopausal female.
150. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 95 µg for one year to a post-menopausal female.
151. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 96 µg for one year to a post-menopausal female.
152. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 97 µg for one year to a post-menopausal female.
153. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 98 µg for one year to a post-menopausal female.
154. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 99 µg for one year to a post-menopausal female.
155. A pharmaceutical kit comprising human parathyroid hormone (1-84) (PTH(1-84)), wherein the PTH(1-84) is formulated as a subcutaneous injection as a daily unit dosage form and is the only therapeutically active compound in the kit, and instructions for administration of the PTH(1-84) at a daily dose of about 100 µg for one year to a post-menopausal female.
156. The kit according to any one of claims 55 to 105, wherein administration of the PTH(1-84) daily for one year to a post-menopausal female increases the bone mineral density of the lumbar spine by about 8%.
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SE9702401-2 | 1997-06-19 | ||
SE9702401A SE9702401D0 (en) | 1997-06-19 | 1997-06-19 | Pharmaceutical use |
CA2294101A CA2294101C (en) | 1997-06-19 | 1998-06-08 | A combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor |
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CA2294101A Division CA2294101C (en) | 1997-06-19 | 1998-06-08 | A combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor |
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CA2698626A1 CA2698626A1 (en) | 1998-12-23 |
CA2698626C true CA2698626C (en) | 2016-02-09 |
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ID=20407482
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CA2294101A Expired - Fee Related CA2294101C (en) | 1997-06-19 | 1998-06-08 | A combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor |
CA2698626A Expired - Fee Related CA2698626C (en) | 1997-06-19 | 1998-06-08 | A combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor |
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CA2294101A Expired - Fee Related CA2294101C (en) | 1997-06-19 | 1998-06-08 | A combined pharmaceutical preparation comprising parathyroid hormone and a bone resorption inhibitor |
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US (8) | US6284730B1 (en) |
EP (2) | EP1001802B1 (en) |
JP (3) | JP4989811B2 (en) |
AT (2) | ATE447410T1 (en) |
AU (1) | AU753477B2 (en) |
CA (2) | CA2294101C (en) |
CY (1) | CY1110287T1 (en) |
DE (2) | DE69841279D1 (en) |
DK (2) | DK1001802T3 (en) |
ES (2) | ES2229511T3 (en) |
HK (2) | HK1029738A1 (en) |
PT (2) | PT1001802E (en) |
SE (1) | SE9702401D0 (en) |
WO (1) | WO1998057656A1 (en) |
ZA (1) | ZA984947B (en) |
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-
1997
- 1997-06-19 SE SE9702401A patent/SE9702401D0/en unknown
-
1998
- 1998-06-08 DE DE69841279T patent/DE69841279D1/en not_active Expired - Lifetime
- 1998-06-08 US US09/125,247 patent/US6284730B1/en not_active Expired - Lifetime
- 1998-06-08 PT PT98929965T patent/PT1001802E/en unknown
- 1998-06-08 JP JP50425999A patent/JP4989811B2/en not_active Expired - Fee Related
- 1998-06-08 ES ES98929965T patent/ES2229511T3/en not_active Expired - Lifetime
- 1998-06-08 DK DK98929965T patent/DK1001802T3/en active
- 1998-06-08 EP EP98929965A patent/EP1001802B1/en not_active Expired - Lifetime
- 1998-06-08 AT AT04017622T patent/ATE447410T1/en active
- 1998-06-08 CA CA2294101A patent/CA2294101C/en not_active Expired - Fee Related
- 1998-06-08 WO PCT/SE1998/001095 patent/WO1998057656A1/en active IP Right Grant
- 1998-06-08 AU AU79458/98A patent/AU753477B2/en not_active Ceased
- 1998-06-08 DE DE69826132T patent/DE69826132T2/en not_active Expired - Lifetime
- 1998-06-08 PT PT04017622T patent/PT1473040E/en unknown
- 1998-06-08 DK DK04017622.4T patent/DK1473040T3/en active
- 1998-06-08 AT AT98929965T patent/ATE275419T1/en active
- 1998-06-08 ES ES04017622T patent/ES2335404T3/en not_active Expired - Lifetime
- 1998-06-08 EP EP04017622A patent/EP1473040B1/en not_active Expired - Lifetime
- 1998-06-08 CA CA2698626A patent/CA2698626C/en not_active Expired - Fee Related
- 1998-06-08 ZA ZA984947A patent/ZA984947B/en unknown
-
2000
- 2000-11-23 HK HK00107524A patent/HK1029738A1/en not_active IP Right Cessation
-
2001
- 2001-08-31 US US09/942,661 patent/US20020002135A1/en not_active Abandoned
-
2003
- 2003-03-18 US US10/389,797 patent/US7018982B2/en not_active Expired - Fee Related
-
2005
- 2005-04-22 HK HK05103473.5A patent/HK1070816A1/en not_active IP Right Cessation
- 2005-12-19 US US11/305,339 patent/US7507715B2/en not_active Expired - Fee Related
-
2009
- 2009-01-09 US US12/351,558 patent/US7749543B2/en not_active Expired - Fee Related
-
2010
- 2010-01-04 JP JP2010000066A patent/JP5525825B2/en not_active Expired - Fee Related
- 2010-01-29 CY CY20101100091T patent/CY1110287T1/en unknown
- 2010-06-23 US US12/822,089 patent/US8153588B2/en not_active Expired - Fee Related
-
2012
- 2012-02-24 US US13/405,093 patent/US8765674B2/en not_active Expired - Fee Related
-
2013
- 2013-10-02 JP JP2013206919A patent/JP2014015479A/en active Pending
-
2014
- 2014-05-22 US US14/285,437 patent/US20140256632A1/en not_active Abandoned
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