AU2005227418A1 - Method for inhibiting bone resorption - Google Patents

Description

S&F Ref: 490011D4

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Merck Co., Inc., of 126 East Lincoln Avenue, Rahway, New Jersey, 07065-0907, United States of America Anastasia G. Daifotis A. John Yates Arthur C. Santora II Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Method for inhibiting bone resorption The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c Q TITLE OF THE INVENTION METHOD FOR INHIBITFNG BONE RESORPTION

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00 00 In o 0 FIELD OF THE INVENTION The present invention relates to oral methods for inhibiting bone resorption in a mammal while minimizing the occurrence of or potential for adverse gastrointestinal effects. These methods comprise orally administering to a mammal in need thereof of a pharmaceutically effective amount of a bisphosphonate as a unit dosage according to a continuous schedule having a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice-monthly dosing. The present invention also relates to pharmaceutical compositions and kits useful for carrying out these methods.

BACKGROUND OF THE INVENTION A variety of disorders in humans and other mammals involve or are associated with abnormal bone resorption. Such disorders include, but are not limited to, osteoporosis, Paget's disease, periprosthetic bone loss or osteolysis, and hypercalcemia of malignancy. The most common of these disorders is osteoporosis, which in its most frequent manifestation occurs in postmenopausal women.

Osteoporosis is a systemic skeletal disease characterized by a low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Because osteoporosis, as well as other disorders associated with bone loss, are chronic conditions, it is believed that appropriate therapy will generally require chronic treatment.

Multinucleated cells called osteoclasts are responsible for causing bone loss through a process known as bone resorption. It is well known that bisphosphonates are selective inhibitors of osteoclastic bone resorption, making these compounds important therapeutic agents in the treatment or prevention of a variety of CN generalized or localized bone disorders caused by or associated with abnormal bone 0 resorption. See H. Fleisch, Bisphosphonates In Bone Disease, From The Laboratory 0 To The Patient, 2nd Edition, Parthenon Publishing (1995), which is incorporated by

OO

0 reference herein in its entirety.

At present, a great amount of preclinical and clinical data exists for the 00 potent bisphosphdnate compound alendronate. Evidence suggests that other bisphosphonates such as risedronate, tiludronate, ibandronate and zolendronate, have many properties in common with alendronate, including high potency as inhibitors of I osteoclastic bone resorption An older bisphosphonate compound, etidronate, also O 10 inhibits bone resorption. However, unlike the more potent bisphosphonates, C etidronate impairs mineralization at doses used clinically, and may give rise to osteomalacia, a condition resulting in an undesirable decrease in bone mineralization.

See Boyce, B. Fogelman, Ralston, S. et al. (1984) Lancet 1(8381), pp. 821-824 (1984), and Gibbs, C. Aaron, J. Peacock, M. (1986) Br. Med. J. 292, pp. 1227- 1229 (1986), both of which are incorporated by reference herein in their entirety.

Despite their therapeutic benefits, bisphosphonates are poorly absorbed from the gastrointestinal tract. See B.J. Gertz et al., Clinical Pharmacology of Alendronate Sodium, Osteoporosis Int., Suppl. 3: S 13-16 (1993) and B.J. Gertz et al., Studies of the oral bioavailability of alendronate, Clinical Pharmacology Therapeutics, vol. 58, number 3, pp. 288-298 (September 1995), which are incorporated by reference herein in their entirety. Intravenous administration has been used to overcome this bioavailability problem. However, intravenous administration is costly and inconvenient, especially when the patient must be given an intravenous infusion lasting several hours on repeated occasions.

If oral administration of the bisphosphonate is desired, relatively high doses must be administered to compensate for the low bioavailability from the gastrointestinal tract. To offset this low bioavailability, it is generally recommended that the patient take the bisphosphonate on an empty stomach and fast for at least minutes afterwards. However, many patients find the need for such fasting on a daily basis to be inconvenient. Moreover, oral administration has been associated with adverse gastrointestinal effects, especially those relating to the esophagus. See Fleisch, Id. These effects appear to be related to. the irritant potential of the bisphosphonate in the esophagus, a problem which is exacerbated by the presence of refluxed gastric acid. For example, the bisphosphonate, pamidronate has been associated with esophageal ulcers. See E.G. Lufkin et al., Pamidronate: An 0 Unrecognized Problem in Gastrointestinal Tolerability, Osteoporosis International, Cl 4: 320-322 (1994), which is incorporated by reference herein in its entirety. Although O not as common, the use of alendronate has been associated with esophagitis and/or 00 esophageal ulcers. See P.C. De Groen, et al., Esophagitis Associated With The Use Of Alendronate, New England Journal of Medicine, vol. 335, no. 124, pp. 1016-1021 (1996), D.O. Castell, Pill Esophagitis The Case of Alendronate, New England 00 Journal of Medicine, vol. 335, no. 124, pp. 1058-1059 (1996), and U.A. Liberman et al., Esophagitis and Alendronate, New England Journal of Medicine, vol. 335, no.

S124, pp. 1069-1070 (1996), which are incorporated by reference herein in their V) 10 entirety. The degree of adverse gastrointestinal effects of bisphosphonates has been 0shown to increase with increasing dose. See C.H. Chestnut et al., Alendronate Treatment of the Postmenopausal Osteoporotic Woman: Effect of Multiple Dosages on Bone Mass and Bone Remodeling, The American Journal of Medicine, vol. 99, pp.

144-152, (August 1995), which is incorporated by reference herein in its entirety.

Also, these adverse esophageal effects appear to be more prevalent in patients who do not take the bisphosphonate with an adequate amount of liquid or who lie down shortly after dosing, thereby increasing the chance for esophageal reflux.

Current oral bisphosphonate therapies generally fall into two categories: those therapies utilizing continuous daily treatment, and those therapies utilizing a cyclic regimen of treatment and rest periods.

The continuous daily treatment regimens normally involve the chronic administration of relatively low doses of the bisphosphonate compound, with the objective of delivering the desired cumulative therapeutic dose over the course of the treatment period. However, continuous daily dosing has the potential disadvantage of causing adverse gastrointestinal effects due to the repetitive, continuous, and additive irritation to the gastrointestinal tract. Also, because bisphosphonates should be taken on an empty stomach followed by fasting and maintenance of an upright posture for at least 30 minutes, many patients find daily dosing to be burdensome. These factors can therefore interfere with patient compliance, and in severe cases even require cessation of treatment.

Cyclic treatment regimens were developed because some bisphosphonates, such as etidronate, when given daily for more than several days, have the disadvantage of actually causing a decline in bone mineralization, i.e.

osteomalacia. U.S. Patent No. 4,761,406, to Flora et al, issued August 2, 1988, which is incorporated by reference herein in its entirety, describes a cyclic regimen developed in an attempt to minimize the decline in bone mineralization while still providing a therapeutic anti-resorptive effect. Generally, cyclic regimens are O characterized as being intermittent, as opposed to continuous treatment regimens, and 00 have both treatment periods during which the bisphosphonate is administered and nontreatment periods to permit the systemic level of the bisphosphonate to return to 00 baseline. However, the cyclic regimens, relative to continuous dosing, appear to result in a decreased therapeutic antiresorptive efficacy. Data on risedronate suggests Sthat cyclic dosing is actually less effective than continuous daily dosing for N maximizing antiresorptive bone effects. See L. Mortensen, et al., Prevention Of Early Postmenopausal Bone Loss By Risedronate, Jounal of Bone and Mineral SResearch, vol. 10, supp. 1, p. s140 (1995), which is incorporated by reference herein in its entirety. Furthermore, these cyclic regimens do not eliminate or minimize adverse gastrointestinal effects, because such regimens typically utilize periods of multiple daily dosing. Also, the cyclic regimens are cumbersome to administer and have the disadvantage of low patient compliance, and consequently compromised therapeutic efficacy. U.S. Patent No. 5,366,965, to Strein, issued November 22, 1994, which is incorpoated by reference herein in its entirety, attempts to address the problem of adverse gastrointestinal effects by administering a polyphosphonate compound, either orally, subcutaneously, or intravenously, according to an intermittent dosing schedule having both a bone resorption inhibition period and a notreatment rest period. However, the regimen has the disadvantage of not being continuous and regular, and requires nontreatment periods ranging from 20 to 120 days. PCT Application No. WO 95/30421, to Goodship et al, published November 16, 1995, which is incorporated by reference herein in its entirety, discloses methods for preventing prosthetic loosening and migration using various bisphosphonate compounds. Administration of a once weekly partial dose of the bisphosphonate is disclosed. However, the reference specifically fails to address the issue of adverse gastrointestinal effects or to disclose administration of larger or multiple dosages.

It is seen from current teachings that both daily and cyclic treatment regimens have shortcomings, and that there is a need for development of a dosing regimen to overcome these shortcomings.

In the present invention, it is found that the adverse gastrointestinal effects that can be associated with daily or cyclic dosing regimens can be minimized by administering the bisphosphonate at a relatively high unit dosage according to a Scontinuous schedule having a dosing interval selected from the group consisting of Sonce-weekly dosing, twice-weekly dosing, biweekly dosing, and twice-monthly O dosing. In other words, it is found that the administration of a bisphosphonate at a 0 high relative dosage at a low relative dosing frequency causes less adverse gastrointestinal effects, particularly esophageal effects, compared to the administration of'a low relative dosage at a high relative dosing frequency. This result 00 _is surprising in view of the teachings suggesting that adverse gastrointestinal effects would be expected to increase as a function of increasing bisphosphonate dosage.

(N1 Such administration methods of the present invention would be especially beneficial in treating patients that have been identified as suffering from or are susceptible to Supper gastrointestinal disorders, e.g. gastrointestinal reflux disease "GERD"), 'i esophagitis, dyspepsia heatburn), ulcers, and other related disorders. In such patients conventional bisphosphonate therapy could potentially exacerbate or induce such upper gastrointestinal disorders.

From a patient lifestyle standpoint, the methods of the present invention would also be more convenient than daily or cyclic dosing regimens.

Patients would be subjected less frequently to the inconvenience of having to take the drug on an empty stomach and having to fast for at least 30 minutes after dosing.

Also, patients would not need to keep track of a complex dosing regimen. The methods of the present invention are likely to have the advantage of promoting better patient compliance, which in turn can translate into better therapeutic efficacy.

It is an object of the present invention to provide methods for inhibiting bone resorption and the conditions associated therewith.

It is another object of the present invention to provide methods for treating abnormal bone resorption and the conditions associated therewith It is another object of the present invention to provide methods for preventing abnormal bone resorption and the conditions associated therewith.

It is another object of the present invention to provide methods which are oral methods.

It is another object of the present invention to provide such methods in humans.

It is another object of the present invention to provide such methods in patients that have been identified as suffering from or are susceptible to upper gastrointestinal disorders, e.g. gastrointestinal reflux disease "GERD"), esophagitis, dyspepsia heatburn), ulcers, and other related disorders.

It is another object of the present invention to provide such methods while minimizing the occurrence of or potential for adverse gastronintestinal effects.

0 It is another object of the present invention to provide such methods 00 comprising a continuous dosing schedule having a dosing interval selected from the group consisting of weekly dosing, twice-weekly dosing, biweekly dosing, and twice- 00 monthly dosing. It is another object of the present invention to provide such methods comprising a continuous dosing schedule having a dosing periodicity ranging from about once every 3 days to about once every 16 days.

It is another object of the present invention to provide such methods wherein the continuous dosing schedule is maintained until the desired therapeutic effect is achieved.

It is another object of the present invention to treat or prevent abnormal bone resorption in an osteoporotic mammal, preferably an osteoporotic human.

It is another object of the present invention to provide pharmaceutical compositions and kits useful in the methods herein.

These and other objects will become readily apparent from the detailed description which follows.

SUMMARY OF THE INVENTION The present invention relates to methods for inhibiting bone resorption in a mammal in need thereof, while minimizing the occurrence of or potential for adverse gastrointestinal effects, said method comprising orally administering to said mammal a pharmaceutically effective amount of a bisphosphonate as a unit dosage according to a continuous schedule having a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twicemonthly dosing, wherein said continuous schedule is maintained until the desired therapeutic effect is achieved for said mammal.

In other embodiments, the present invention relates to methods comprising a continuous dosing schedule having a dosing periodicity ranging from about once every 3 days to about once every 16 days.

In other embodiments, the present invention relates to methods for treating abnormal bone resorption in a mammal in need of such treatment.

In other embodiments, the present invention relates to methods for preventing abnormal bone resorption in a mammal in need of such prevention.

o In other embodiments, the present invention relates to such methods Suseful in humans.

0 In other embodiments, the present invention relates to such methods 00 useful in humans indentified as having or being susceptible to upper gastrointestinal disorders.

In dther embodiments, the present invention relates to methods for 00 treating or preventing osteoporosis in a mammal.

In other embodiments, the present invention relates to methods for C treating or preventing osteoporosis in a human.

V 10 In other embodiments, the present invention relates to methods for O inhibiting bone resorption, or treating or preventing abnormal bone resorption in a human comprising administering to said human from about 8.75 mg to about 140 mg, on an alendronic acid active basis, of a bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof.

In other embodiments the present invention relates to a pharmaceutical composition comprising from about 8.75 mg to about 140 mg, on an alendronic acid active basis, of a bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof.

All percentages and ratios used herein, unless otherwise indicated, are by weight. The invention hereof can comprise, consist of, or consist essentially of the essential as well as optional ingredients, components, and methods described herein.

BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a photomicrograph (total magnification 270X) of canine esophagus tissue (paraffin embedded and stained with hematoxylin and eosin) from an animal sacrificed immediately after infusion of the last of five separate dosages of mL of simulated gastric juice administered on five consecutive days.

FIG. 2 is a photomicrograph (total magnification 270X) of canine esophagus tissue (paraffin embedded and stained with hematoxylin and eosin) from an animal sacrificed immediately after infusion of the last of five separate dosages of mL of 0.20 mg/mL alendronate in simulated gastric juice administered on five consecutive days.

FIG. 3 is a photomicrograph (total magnification 270X) of canine esophagus tissue (paraffin embedded and stained with hematoxylin and eosin) from an C animal sacrificed 24 hours after infusion with a single dosage of 50 ml.. of 0.80 0 mg/mL alendronate in simulated gastric juice.

O FIG. 4 is a photomicrograph (total magnification 270X) of canine 00 Sesophagus tissue (paraffin embedded and stained with hematoxylin and cosin) from an animal sacrificed 7 days after infusion with a single dosage of 50 mL of 0.80 mg/mL 00 alendronate in simulated gastric juice.

FIG. 5 is a photomicrograph (total magnification 270X) of canine esophagus tissue (paraffin embedded and stained with hematoxylin and eosin) from an 1 animal sacnified 7 days after infusion of the last of 4 separate dosages of 50 mL of O 10 0.80 mg/mL alendronate in simulated gastric juice administered once per week, i.e.

C once every 7 days.

FIG. 6 is a photomicrograph (total magnification 270X) of canine esophagus tissue (paraffin embedded and stained with hematoxylin and eosin) from an animal sacrified 4 days after infusion of the last of 8 separate dosages of 50 mL of 0.40 mg/mL alendronate in simulated gastric juice administered twice per week, i.e.

once every 3-4 days.

FIG. 7 is a photomicrograph (total magnification 270X) of canine esophagus tissue (paraffin embedded and stained with hematoxylin and eosin) from an animal sacrificed immediately after infusion of the last of five separate dosages of mL of 0.20 mg/mL risedronate in simulated gastric juice administered on five consecutive days.

FIG. 8 is a photomicrograph (total magnification 270X) of canine esophagus tissue (paraffin embedded and stained with hematoxylin and eosin) from an animal sacrificed immediately after infusion of the last of five separate dosages of mL of 4.0 mg/mL tiludronate in simulated gastric juice administered on five consecutive days.

DESCRIPTION OF THE INVENTION The present invention relates to a method, preferably an oral method, for inhibiting bone resorption in a mammal in need thereof, while minimizing the occurrence of or potential for adverse gastrointestinal effects. The present invention relates to methods of treating or preventing abnormal bone resorption in a mammal in need of such treatment or prevention. The methods of the present invention comprise orally administering to a mammal a pharmaceutically effective amount of a bisphosphonate as a unit dosage, wherein said dosage is administered according to a J continuous schedule having a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice-monthly O dosing. In other embodiments, the present invention relates to methods comprising a 00 continuous dosing schedule having a dosing periodicity ranging from about once every 3 days to about once every 16 days. Typically, the continuous dosing schedule is maintained until'the desired therapeutic effect is achieved for the mammal.

00 The present invention utilizes higher unit dosages of the bisphosphonate at each dosing point than has heretofore been typically administered, C yet because of the dosing schedule chosen, the potential for adverse gastrointestinal 10 effects are minimized. Moreover, the method is more convenient because the 0 disadvantages associated with daily dosing are minimized.

The methods of the present invention are generally administered to mammals in need of bisphosphonate therapy. Preferably the mammals are human patients, particularly human patients in need of inhibiting bone resorption, such as patients in need of treating or preventing abnormal bone resorption.

The administration methods of the present invention are especially useful in administering bisphosphonate therapy to human patients that have been identified as suffering from or are susceptible to upper gastrointestinal disorders, e.g.

GERD, esophagitis, dyspepsia, ulcers, etc. In such patients conventional bisphosphonate therapy could potentially exacerbate or induce such upper gastrointestinal disorders.

The term "pharmaceutically effective amount", as used herein, means that amount of the bisphosphonate compound, that will elicit the desired therapeutic effect or response when administered in accordance with the desired treatment regimen. A preferred pharmaceutically effective amount of the bisphosphonate is a bone resorption inhibiting amount.

The term "minimize the occurrence of or potential for adverse gastrointestinal effects", as used herein, means reducing, preventing, decreasing, or lessening the occurrence of or the potential for incurring unwanted side effects in the gastrointestinal tract, i.e. the esophagus, stomach, intestines, and rectum, particularly the upper gastrointestinal tract, i.e. the esophagus and stomach. Nonlimiting adverse gastrointestinal effects include, but are not limited to GERD, esophagitis, dyspepsia, ulcers, esophageal irritation, esophageal perforation, abdominal pain, and constipation.

The term "abnormal bone resorption", as used herein means a degree of O bone resorption that exceeds the degree of bone formation, either locally, or in the 0 skeleton as a whole. Alternatively, "abnormal bone resorption" can be associated with 0the formation of bone having an abnormal structure.

The term "bone resorption inhibiting", as used herein, means treating 00 or preventing bone resorption by the direct or indirect alteration of osteoclast formation or activity. Inhibition of bone resorption refers to treatment or prevention of bone loss, especially the inhibition of removal of existing bone either from the mineral phase and/or the organic matrix phase, through direct or indirect alteration of osteoclast formation or activity.

SThe terms "continuous schedule" or "continuous dosing schedule", as used herein, mean that the dosing regimen is repeated until the desired therapeutic effect is achieved. The continuous schedule or continuous dosing schedule is distinguished from cyclical or intermittent administration.

The term "until the desired therapeutic effect is achieved", as used herein, means that the bisphosphonate compound is continuously administered, according to the dosing schedule chosen, up to the time that the clinical or medical effect sought for the disease or condition is observed by the clinician or researcher.

For methods of treatment of the present invention, the bisphosphonate compound is continuously administered until the desired change in bone mass or structure is observed. In such instances, achieving an increase in bone mass or a replacement of abnormal bone structure with more normal bone structure are the desired objectives.

For methods of prevention of the present invention, the bisphosphonate compound is continuously administered for as long as necessary to prevent the undesired condition.

In such instances, maintenance of bone mass density is often the objective.

Nonlimiting examples of administration periods can range from about 2 weeks to the remaining lifespan of the mammal. For humans, administration periods can range from about 2 weeks to the remaining lifespan of the-human, preferably from about 2 weeks to about 20 years, more preferably from about 1 month to about 20 years, more preferably from about 6 months to about 10 years, and most preferably from about 1 year to about 10 years.

Methods of the Present Invention The present invention comprises methods for inhibiting bone resorption in mammals. The present invention also comprises treating abnormal bone 0O rcsorption in mammals. The present invention also comprises methods for preventino abnormal bone resorption in mammals. In preferred embodiments of the present 0 invention, the mammal is a human: 00 The methods of the present invention do not have the disadvantages of current methods of treatment which can cause or increase the potential for adverse gastrointestinal effects or which require cumbersome, irregular, or complicated dosing Sregimens.

The present invention comprises a continuous dosing schedule whereby a unit dosage of the bisphosphonate is regularly administered according to a dosing interval selected from the group consisting of once-weekly dosing, twiceweekly dosing, biweekly dosing, and twice-monthly dosing.

By once-weekly dosing is meant that a unit dosage of the bisphosphonate is administered once a week, i.e. one time during a seven day period, preferably on the same day of each week. In the once-weekly dosing regimen, the unit dosage is generally administered about every seven days. A nonlimiting example of a once-weekly dosing regimen would entail the administration of a unit dosage of the bisphosphonate every Sunday. It is preferred that the unit dosage is not administered on consecutive days, but the once-weekly dosing regimen can include a dosing regimen in which unit dosages are administered on two consecutive days falling within two different weekly periods.

By twice-weekly dosing is meant that a unit dosage of the bisphosphonate is administered twice a week, i.e. two times during a seven day period, preferably on the same two days of each weekly period. In the twice-weekly dosing regimen, each unit dosage is generally administered about every three to four days. A nonlimiting example of a twice-weekly dosing regimen would entail the administration of a unit dosage of the bisphosphonate every Sunday and Wednesday.

It is preferred that the unit dosages are not administered on the same or consecutive days, but the twice-weekly dosing regimen can include a dosing regimen in which unit dosages are administered on two consecutive days within a weekly period or different weekly periods.

By biweekly dosing is meant that a unit dosage of the bisphosphonate is administered once during a two week period, i.e. one time during a fourteen day period, preferably on the same day during each two week period. In the twice-weekly dosing regimen, each unit dosage is generally administered about every fourteen days.

A nonlimiting example of a biweekly dosing regimen would entail the administration -11of a unit dosage of the bisphosphonate every other Sunday. It is preferred that the unit dosage is not administered on consecutive days, but the biweekly dosing regimen can 0 include a dosing regimen in which the unit dosage is administered on two consecutive 00 days within two different biweekly periods.

By twice-monthly dosing is meant that a unit dosage of the 00 bisphosphonate is'administered twice, i.e. two times, during a monthly calendar period. With the twice-monthly regimen, the doses are preferably given on the same two dates of each month. In the twice-monthly dosing regimen, each unit dosage is c generally administered about every fourteen to sixteen days. A nonlimiting example of a biweekly dosing regimen would entail dosing on or about the first of the month and on or about the fifteenth, i.e. the midway point, of the month. It is preferred that the unit dosages are not administered on the same or consecutive days but the twicemonthly dosing regimen can include a dosing regimen in which the unit dosages are administered on two consecutive days within a monthly period, or different monthly periods. The twice-monthly regimen is defined herein as being distinct from, and not encompassing, the biweekly dosing regimen because the two regimens have a different periodicity and result in the administration of different numbers of dosages over long periods of time. For example, over a one year period, a total of about twenty four dosages would be administered according to the twice-monthly regimen (because there are twelve calendar months in a year), whereas a total of about twenty six dosages would be administered according to the biweekly dosing regimen (because there are about fifty-two weeks in a year).

In further embodiments or descriptions of the present invention, the unit dosage is given with a periodicity ranging from about once every 3 days to about once every 16 days.

The methods and compositions of the present invention are useful for inhibiting bone resorption and for treating and preventing abnormal bone resorption and conditions associated therewith. Such conditions include both generalized and localized bone loss. Also, the creation of bone having an abnormal structure, as in Paget's disease, can be associated with abnormal bone resorption. The term "generalized bone loss" means bone loss at multiple skeletal sites or throughout the skeletal system. The term "localized bone loss" means bone loss at one or more specific, defined skeletal sites.

Generalized boss loss is often associated with osteoporosis.

Osteoporosis is most common in post-menopausal women, wherein estrogen O production has been greatly diminished. However, osteoporosis can also be steroidinduced and has been observed in males due to age. Osteoporosis can be induced by O disease, e.g. rheumatoid arthritis, it can be induced by secondary causes, e.g., OQ glucocorticoid therapy, or i.t can come about with no identifiable cause, i.e. idiopathic C' ,5 osteoporosis. In the present invention, preferred methods include the treatment or prevention of abn6rmal bone resorption in osteoporotic humans.

00 Localized bone loss has been associated with periodontal disease, with bone fractures, and with periprosthetic osteolysis (in other words where bone C resorption has occured in proximity to a prosthetic implant).

t' 10 Generalized or localized bone loss can occur from disuse, which is often a problem for those confined to a bed or a wheelchair, or for those who have an immobilized limb set in a cast or in traction.

The methods and compositions of the present invention are useful for treating and or preventing the following conditions or disease states: osteoporosis, which can include post-menopausal osteoporosis, steroid-induced osteoporosis, male osteoporosis, disease-induced osteoporosis, idiopathic osteoporosis; Paget's disease; abnormally increased bone turnover; periodontal disease; localized bone loss associated with periprosthetic osteolysis; and bone fractures.

The methods of the present invention are intended to specifically exclude methods for the treatment and/or prevention of prosthesis loosening and prosthesis migration in mammals as described in PCT application WO 95/30421, to Goodship et al, published November 16, 1995, which is incorporated by reference herein in its entirety.

Bisphosphonates The methods and compositions of the present invention comprise a bisphosphonate. The bisphosphonates of the present invention correspond to the chemical formula P0 3

H

2

A-C-X

P0 3

H

2 -13c, 0 wherein 0 A and X are independently selected from the group consisting of IH, oo OH, halogen, NH2, SH, phenyl, CI-C30 alkyl, CI-C30 substituted alkyl, alkyl or dialkyl substituted NH2, CI-CI0 alkoxy, CI-CI0 alkyl or phenyl substituted 00 thio, CI-C10 alkyl substituted phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, and benzyl.

In the foregoing chemical formula, the alkyl groups can be straight, branched, or cyclic, provided sufficient atoms are selected for the chemical formula.

O 10 The C1-C30 substituted alkyl can include a wide variety of substituents, nonlimiting Sexamples which include those selected from the group consisting of phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, NH2, C1-C10 alkyl or dialkyl substituted NH2, OH, SH, and C1-C10 alkoxy.

In the foregoing chemical formula, A can include X and X can include A such that the two moieties can form part of the same cyclic structure.

The foregoing chemical formula is also intended to encompass complex carbocyclic, aromatic and hetero atom structures for the A and/or X substituents, nonlimiting examples of which include naphthyl, quinolyl, isoquinolyl, adamantyl, and chlorophenylthio.

Preferred structures are those in which A is selected from the group consisting of H, OH, and halogen, and X is selected from the group consisting of C1alkyl, C1-C30 substituted alkyl, halogen, and C1-C10 alkyl or phenyl substituted thio.

More preferred structures are those in which A is selected from the group consisting of H, OH, and Cl, and X is selected from the group consisting of C1alkyl, C1-C30 substituted alkyl, CI, and chlorophenylthio.

Most preferred is when A is OH and X is a 3-aminopropyl moiety, so that the resulting compound is a 4-amino-l,-hydroxybutylidene- 1,-bisphosphonate, i.e. alendronate.

Pharmaceutically acceptable salts and derivatives of the bisphosphonates are also useful herein. Nonlimiting examples of salts include those selected from the group consisting alkali metal, alkaline metal, ammonium, and mono-, di, tri-, or tetra-CI-C30-alkyl-substituted ammonium. Preferred salts are those selected from the group consisting of sodium, potassium, calcium, magnesium, and 0 ammonium salts. Nonlimiting examples of derivatives include those selected from the group consisting of esters, hydrates, and amides.

0 "Pharmaceutically acceptable" as used herein means that the salts and 00 derivatives of the bisphosphonates have the same general pharmacological properties as the free acid form from which they are derived and are acceptable from a toxicity viewpoint.

00 It should be noted that the terms "bisphosphonate" and "bisphosphonates", as used herein in referring to the therapeutic agents of the present invention are meant to also encompass diphosphonates, biphosphonic acids, and n 10 diphosphonic acids, as well as salts and derivatives of these materials. The use of a specific nomenclature in referring to the bisphosphonate or bisphosphonates is not meant to limit the scope of the present invention, unless specifically indicated.

Because of the mixed nomenclature currently in use by those or ordinary skill in the art, reference to a specific weight or percentage of a bisphosphonate compound in the present invention is on an acid active weight basis, unless indicated otherwise herein.

For example, the phrase "about 70 mg of a bone resorption inhibiting bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof, on an alendronic acid active weight basis" means that the amount of the bisphosphonate compound selected is calculated based on 70 mg of alendronic acid.

Nonlimiting examples of bisphosphonates useful herein include the following: Alendronic acid, 4-amino-l-hydroxybutylidene-1,1-bisphosphonic acid.

Alendronate (also known as alendronate sodium or monosodium trihydrate), 4-amino-l-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate.

Alendronic acid and alendronate are described in U.S. Patents 4,922,007, to Kieczykowski et al., issued May 1, 1990, and 5,019,651, to Kieczykowski, issued May 28, 1991, both of which are incorporated by reference herein in their entirety.

Cycloheptylaminomethylene- 1,l-bisphosphonic acid, YM 175, Yamanouchi (cimadronate), as described in U.S. Patent 4,970,335, to Isomura et al., issued November 13, 1990, which is incorporated by reference herein in its entirety.

20002YIB l, 1-dichloromethylene- 1, 1-diphosphonic. acid (clodronic acid), and the disodium salt (clodronate, Procter and Gamble), are described in Belgium O Patent 672,205 (1966) and J. Org. Chemn 32, 4111 (1967), both of which are 00 incorporated by reference herein in their entirety.

1-hydroxy-3-(-pyrrolidinyl)-propylidenc-1,1 -bisphosphonic acid (EB-1053).

00 I -hydroxyethane- 1, 1-diphosphonic acid (etidronic acid).

I -hydroxy-3-(N-methyl-N-pentylamino)propylidene 1, I bisphosphonic acid, also known as BM-210955, Boehringer-Mannheim 1 10 (ibandronate), is described in U.S. Patent No. 4,927,814, issued May 22, 1990, O which is incorporated by reference herein in its entirety.

6-amino-1-hydroxyhexylidene- 1,1-bisphosphonic acid (neridronate).

3-(dimethylamino)-1-hydroxypropylidene- 1, 1-bisphosphonic acid (olpadronate).

3-amino- -hydroxypropylidene- 1, 1-bisphosphonic acid (pamidronate).

[2-(2-pyridinyl)ethylidene]-1,1-bisphosphonic acid (piridronate) is described in U.S. Patent No. 4,761,406, which is incorporated by reference in its entirety.

1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid (risedronate).

(4-chlorophenyl)thiomethane-1,1 -disphosphonic acid (tiludronate) as described in U.S. Patent 4,876,248, to Breliere et al., October 24, 1989, which is incorporated by reference herein in its entirety.

1-hydroxy-2-( I H-imidazol- 1 -yl)ethylidene- 1,1 -bisphosphonic acid (zolendronate).

Preferred are bisphosphonates selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, risedronate, piridronate, pamidronate, zoledronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

More preferred is alendronate, ibandronate, risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

More preferred is alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof.

-16- 20002YIB o Most preferred is alcndronate monosodium trihydrate.

In other embodiments, other preferred salts are the sodium salt of O ibandronate, and risedronate monosodium hemi-pentahydrate the 2.5 hydrate of 00 the monosodium salt).

Pharmaceutical Cbmpositions

OO

0 Compositions useful in the present invention comprise a S. pharmaceutically effective amount of a bisphosphonate. The bisphosphonate is Cl typically administered in admixture with suitable pharmaceutical diluents, excipients, n 10 or carriers, collectively referred to herein as "carrier materials", suitably selected with Srespect to oral administration, i.e. tablets, capsules, elixirs, syrups, effervescent compositions, powders, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of a tablet, capsule, or powder, the active ingredient can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, croscarmellose sodium and the like; for oral administration in liquid form, elixirs and syrups, effervescent compositions, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, buffers, coatings, and coloring agents can also be incorporated. Suitable binders can include starch, gelatin, natural sugars such a glucose, anhydrous lactose, free-flow lactose, beta-lactose, and corn sweeteners, natural and synthetic gums, such as acacia, guar, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. A particularly preferred tablet formulation for alendronate monosodium trihydrate is that described in U.S. Patent No. 5,358,941, to Bechard et al, issued October 25, 1994, which is incorporated by reference herein in its entirety. The compounds used in the present method can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropyl-methacrylamide, and the like.

The precise dosage of the bisphonate will vary with the dosing schedule, the oral potency of the particular bisphosphonate chosen, the age, size, sex Sand condition of the mammal or human, the nature and severity of the disorder to be treated, and other relevant medical and physical factors. Thus, a precise O pharmaceutically effective amount cannot be specified in advance and can be readily 00 determined by the caregiver or clinician. Appropriate amounts can be determined by routine experimentation from animal models and human clinical studies. Generally, 00 an appropriate amount of bisphosphonate is chosen to obtain a bone resorption inhibiting effect, i.e. a bone resorption inhibiting amount of the bisphosphonate is administered. For humans, an effective oral dose of bisphosphonate is typically from C about 1.5 to about 6000 pg/kg body weight and preferably about 10 to about 2000 i 10 Ag/kg of-body weight.

SFor human oral compositions comprising alendronate, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable derivatives thereof, a unit dosage typically comprises from about 8.75 mg to about 140 mg of the alendronate compound, on an alendronic acid active weight basis, i.e. on the basis of the corresponding acid.

For human oral compositions comprising ibandronate, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable derivatives thereof, a unit dosage typically comprises from about 3.5 mg to about 200 mg of the ibandronate compound, on an ibandronic acid active weight basis, i.e. on the basis of the corresponding acid.

For human oral compositions comprising risedronate, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable derivatives thereof, a unit dosage typically comprises from about 3.5 mg to about 200 mg of the risedronate compound, on a risedronic acid active weight basis, i.e. on the basis of the corresponding acid.

For once-weekly dosing, an oral unit dosage comprises from about 17.5 mg to about 70 mg of the alendronate compound, on an alendronic acid active weight basis. Examples of weekly oral dosages include a unit dosage which is useful for osteoporosis prevention comprising about 35 mg of the alendronate compound, and a unit dosage which is useful for treating osteoporosis comprising about 70 mg of the alendronate compound.

For twice-weekly dosing, an oral unit dosage comprises from about 8.75 mg to about 35 mg of the alendronate compound, on an alendronic acid active weight basis. Examples of twice-weekly oral dosages include a unit dosage which is useful for osteoporosis prevention comprising about 17.5 mg of the alendronate -18- O compound, and a unit dosage which is useful for osteoporosis treatment, comprising about 35 mg of the alendronate compound.

O For biweekly or twice-monthly dosing, an oral unit dosage comprises 00 from about 35 mg to about 140 mg of the alendronate compound, on an alendronic N 5 acid active weight basis. Examples of biweekly or twice-monthly oral dosages include a unit dosage which is useful for osteoporosis prevention comprising about 00 Smg of the alendronate compound, and a unit dosage which is useful for osteoporosis treatment, comprising about 140 mg of the alendronate compound.

C For once-weekly dosing, an oral unit dosage comprises from about 7 V) 10 mg to about 100 mg of the ibandronate compound, on an ibandronic acid active Sweight basis, i.e. calculated on the basis of the corresponding acid. Examples of weekly oral dosages include a unit dosage which is useful for inhibiting bone resorption, and treating and preventing osteoporosis selected from the group consisting of 35 mg, 40 mg, 45 mg, or 50 mg.

For once-weekly dosing, an oral unit dosage comprises from about 7 mg to about 100 mg of the risedronate compound, on a risedronic acid active weight basis, i.e. calculated on the basis of the corresponding acid. Examples of weekly oral dosages include a unit dosage which is useful for inhibiting bone resorption, and treating and preventing osteoporosis selected from the group consisting of 35 mg, mg, 45 mg, or 50 mg.

Nonlimiting examples of oral compositions comprising alendronate, as well as other bisphosphonates, are illustrated in the Examples, below.

Sequential Administration Of Histamine H2 Receptor Blockers And/Or Proton Pump Inhibitors With Bisphosphonates In further embodiments, the methods and compositions of the present invention can also comprise a histamine H2 receptor blocker antagonist) and/or a proton pump inhibitor. Histamine H2 receptor blockers and proton pump inhibitors are well known therapeutic agents for increasing gastric pH. See L.J. Hixson, et al., Current Trends in the Pharmacotherapy for Peptic Ulcer Disease, Arch. Intern. Med., vol. 152, pp. 726-732 (April 1992), which is incorporated by reference herein in its entirety. It is found in the present invention that the sequential oral administration of a histamine H2 receptor blocker and/or a proton pump inhibitor, followed by a bisphosphonate can help to further minimize adverse gastrointestinal effects. In these embodiments, the histamine H2 receptor blocker and/or proton pump inhibitor is Sadministered from about 30 minutes to about 24 hours prior to the administration of the bisphosphonate. In more preferred embodiments, the histamine H-2 receptor O blocker and/or proton pump inhibitor is administered from about 30 minutes to about 00 12 hours prior to the administration of the bisphonate.

The dosage of the histamine H2 receptor blocker and/or proton pump 00 inhibitor will depdnd upon the particular compound selected and factors associated with the mammal to be treated, i.e. size, health, etc.

Nonlimiting examples of histamine H2 receptor blockers and/or proton Spump inhibitors include those selected from the group consisting of cimetidine, famotidine, nizatidine, ranitidine, omeprazole, and lansoprazole.

Treatment Kits In further embodiments, the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention. Such kits are especially suited for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of unit dosages. Such kits can include a card having the dosages oriented in the order of their intended use.

An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered. Alternatively, placebo dosages, or calcium or dietary supplements, either in a form similar to or distinct from the bisphosphonate dosages, can be included to provide a kit in which a dosage is taken every day. In those embodiments including a histamine H2 receptor and/or proton pump inhibitor, these agents can be included as part of the kit.

EXAMPLES

The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention as many variations thereof are possible without departing from the spirit and scope of the invention.

EXAMPLE 1 Esophageal Irritation Potential 0 The esophageal irritation potential of the bisphosphonates is evaluated 1 5 using a dog model.

The experiments demonstrate the relative irritation potential of the 0_ following dosing regimens: placebo (Group a single high concentration dosage of N" alendronate monosodium trihydrate (Group a low concentration dosage of C alendronate monosodium trihydrate administered for five consecutive days (Groups 3 Cl S10 and a high concentration dosage of alendronate monosodium trihydrate administered once per week for four weeks (Group a mid-range concentration l dosage of alendronate monosodium trihydrate administered twice per week for four weeks (Group a low dosage of risedronate sodium administered for five consecutive days (Group and a low dosage of tiludronate disodium administered for five consecutive days (Group 8).

The following solutions are prepared: simulated gastric juice (pH about i.e. the control solution.

simulated gastric juice (pH about 2) containing about 0.20 mg/mL of alendronate monosodium trihydrate on an alendronic acid active basis.

simulated gastric juice (pH about 2) containing about 0.80 mg/mL of alendronate monosodium trihydrate on an alendronic acid active basis.

simulated gastric juice (pH about 2) containing about 0.40 mg/mL of alendronate monosodium trihydrate on an alendronic acid active basis.

simulated gastric juice (pH about 2) containing about 0.20 mg/mL of risedronate sodium on a risedronic acid active basis.

simulated gastric juice (pH about 2) containing about 4.0 mg/mL of tiludronate disodium on a tiludronic acid active basis.

The simulated gastric juice is prepared by dissolving about 960 mg of pepsin (L- 585,228000B003, Fisher Chemical) in about 147 mL of 0.90 (wt NaCI (aqueous), adding about 3mL of 1.0 M HCI (aqueous), and adjusting the volume to about 300 mL with deionized water. The pH of the resulting solution is measured and if necessary is adjusted to about 2 using 1.0 M HCI (aqueous) or 1.0 M NaOH (aqueous).

The animals used in the experiments are anesthetized and administered about 50 mL of the appropriate solution over about 30 minutes by infusion into the esophagus using an infusion pump and a rubbcr catheter. The following treatmeni 0 experiments are run:

O

00 0, Group 1: This control group contains four animals. Each animal is administered a dosage of about 50 mL of simulated gastric juice [solution 00 on each of five consecutive days. The animals are sacrificed immediately after the last dose is administered.

1 C Group 2: This group contains four animals. Each animal is S 10 administered a dosage of about 50 mL of simulated gastric juice containing CI about 0.20 mg/mL of alendronate [solution on each of five consecutive days. The animals are sacrificed immediately after the last dose is administered.

Group 3: This group contains five animals. Each animal is administered a dosage of about 50 mL of simulated gastric juice containing about 0.80 mg/mL of alendronate [solution on a single treatment day. The animals are sacrificed about 24 hours after the dose is administered.

Group 4: This group contains five animals. Each animal is administered a dosage of about 50 mL of simulated gastric juice containing about 0.80 mg/mL of alendronate [solution on a single treatment day. The animals are sacrificed about 7 days after the dose is administered.

Group 5: This group contains six animals. Each animal is administered a dosage of about 50 mL of simulated gastric juice containing about 0.80 mg/mL of alendronate [solution once per week, i.e. every seven days, for four weeks. The animals are administered a total of four dosages. The animals are sacrificed about 7 days after the last dose is administered.

Group 6: This group contains six animals. Each animal is administered a dosage of about 50 mL of simulated gastric juice containing about 0.40 mg/mL of alendronate [solution twice per week, i.e. every three to four days, for four weeks. The animals are administered a total of 0 eight dosages. The animals arc sacrificed about four days after the last dose is administered.

O

00 Group 7: This group contains eight animals. Each animal is S 5 administered a dosage of about 50 mL of simulated gastric juice containing about 0.20"mg/mL of risedronate [solution on each of five consecutive 00 days. The animals are sacrificed immediately after the last dose is administered.

10 Group 8: This group contains four animals. Each animal is

O

administered a dosage of about 50 mL of simulated gastric juice containing about 4.0 mg/mL of tiludronate [solution on each of five consecutive days.

The animals are sacrificed immediately after the last dose is administered.

The esophagus from each sacrificed animal is removed and prepared for histopathology using standard techniques by embedding the tissue in paraffin, staining with hematoxylin and eosin. The sections are examined microscopically.

The histopathology results are summarized in Table 1.

For the Group 1 animals (control group), the photomicrographs show that the esophagus is normal with an intact epithelium and absence of inflammatory cells in the submucosa. FIG. 1 is a representative photomicrograph from a Group 1 animal.

For the Group 2 animals, the photomicrographs show that the esophagus exhibits deep ulceration of the epithelial surface and marked submucosal inflammation and vacuolation. FIG. 2 is a representative photomicrograph from a Group 2 animal.

For the Group 3 animals, the photomicrographs show that the esophagus has an intact epithelial surface with very slight submucosal inflammation and vacuolation. FIG. 3 is a representative photomicrograph from a Group 3 animal.

For the Group 4 animals, the photomicrographs show that the esosphagus has an intact epithelium with either minimal inflammation (two of the five animals) or no inflammation (three of the five animals) and no vacuolation. FIG. 4 is a representative photomicrograph from a Group 4 animal exhibiting minimal inflammation.

SFor the Group 5 animals, the photomicrographs show that the 0 esophagus is normal with an intact epithelium and absence of inflammatory cells in O the submucosa. FIG. 5 is a representative photomicrograph from a Group 5 animal.

0 For the Group 6 animals, the photomicrographs show that the esophagus exhibits deep ulceration of the epithelial surface and marked submucosal 00 inflammation and vacuolation. FIG. 6 is a representative photomicrograph from a Group 6 animal.

C" For the Group 7 animals, the photomicrographs show that the esophagus exhibits deep ulceration of the epithelial surface and marked submucosal S 10 inflammation and vacuolation. FIG. 7 is a representative photomicrograph from a cl Group 7 animal.

For the Group 8 animals, the photomicrographs show that the esophagus exhibits slight ulceration of the epithelial surface and slight submucosal inflammation and vacuolation. FIG. 8 is a representative photomicrograph from a Group 8 animal.

These experiments demonstrate that considerably less esophageal irritation (comparable to control Group 1)is observed from the administration of a single high concentration dosage of alendronate (Groups 3 and 4) versus administration of low concentration dosages on consecutive days (Group These experiments also demonstrate consideraly less esophageal irritation is observed from the administration of a single high concentration of alendronate on a weekly basis (Group 5) or twice-weekly basis (Group 6) versus administration of low concentration dosages on consecutive days (Group These experiments also demonstrate that when other bisphosphonates such as risedronate (Group 7) or tiludronate (Group 8) are administered at low dosages on consecutive days that the esophageal irritation potential is high.

-24- Table 1.

Esophageal Irritation Potential Studies Group Active Agent Dosing Sacrifice Histo-pathology mg/mL Schedule Time 1 0 IX daily immediately Normal. Intact epithelium and for 5 days after last absence of inflammatory cells dosing in the submucosa.

2 Alendronate IX daily immediately Deep ulceration of epithelial 0.20 for 5 days after last surface. Marked submucosal dosing inflammation and vacuolation.

3 Alendronate IX 24 hours after Intact epithelial surface with 0.80 dosing very slight submucosal inflammation and vacuolation.

4 Alendronate 1X 7 days after Intact epithelium with either 0.80 dosing minimal inflammation (2 of animals) or no inflammation (3 of 5 animals) and no vacuolation.

Alendronate IX weekly 7 days after Intact epithelium with no 0.80 for a total last dosing inflammation and no of 4 doses vacuolation.

6 Alendronate 2X weekly immediately Deep ulceration of epithelial 0.40 for 4 after last surface. Marked submucosal weeks dosing inflammation and vacuolation.

7 Risedronate IX daily immediately Deep ulceration of epithelial 0.20 for 5 days after last surface (4 of 8 animals).

dosing Marked submucosal inflammation and vacuolation.

8 (n=4) Tiludronate 4.0 IX daily for 5 days 24 hours after last dosing Slight submucosal inflammation and vacuolation (3 of 4 animals, including 1 of these animals with slight ulceration).

SEXAMPLE 2 O Once-weekly dosing regimen.

00

N

Treatment of osteoporosis.

oo Aiendronate tablets or liquid formulations containing about 70 mg of alendronate, on an alendronic acid active basis, are prepared (see EXAMPLES 7 and The tablets or liquid formulations are orally administered to a human patient onceweekly, i.e. preferably about once every seven days (for example, every Sunday), for a period of at least one year. This method of administration is useful and convenient for treating osteoporosis and for minimizing adverse gastrointestinal effects, particularly adverse esophageal effects. This method is also useful for improving patient acceptance and compliance.

Prevention of osteoporosis.

Alendronate tablets or liquid formulations containing about 35 mg of alendronate, on an alendronic acid active basis, are prepared (see EXAMPLES 7 and The tablets or liquid formulations are orally administered to a human patient onceweekly, i.e. preferably about once every seven days (for example, every Sunday), for a period of at least one year. This method of administration is useful and convenient for preventing osteoporosis and for minimizing adverse gastrointestinal effects, particularly adverse esophageal effects. This method is also useful for improving patient acceptance and compliance.

EXAMPLE 3 Twice-weekly dosing regimen.

Treatment of osteoporosis.

Alendronate tablets or liquid formulations containing about 35 mg of alendronate, on an alendronic acid active basis, are prepared (see EXAMPLES 7 and The tablets or liquid formulations are orally administered to a human patient twice-weekly, preferably about once every three or four days (for example, every Sunday and Wednesday), for a period of at least one year. This method of administration is useful and convenient for treating osteoporosis and for minimizing O adverse gastrointestinal effects, particularly adverse esophageal cffects. This method C'l is also useful for improving patient acceptance and compliance.

O

O

00 Prevention of osteoporosis.

Alendronate tablets or liquid formulations containing about 17.5 mg of alendronate, on ah alendronic acid active basis, are prepared (see EXAMPLES 7 and 00 The tablets or liquid formulations are orally administered to a human patient twice-weekly, preferably about once every three or four days (for example, every c Sunday and Wednesday), for a period of at least one year. This method of 10 administration is useful and convenient for preventing osteoporosis and for 0minimizing adverse gastrointestinal effects, particularly adverse esophageal effects.

This method is also useful for improving patient acceptance and compliance.

EXAMPLE 4 Biweekly dosing regimen Treatment of osteoporosis.

Alendronate tablets or liquid formulations containing about 140 mg of alendronate, on an alendronic acid active basis, are prepared (see EXAMPLES 7 and The tablets or liquid formulations are orally administered to a human patient biweekly, i.e. preferably about once every fourteen days (for example, on alternate Sundays), for a period of at least one year. This method of administration is useful and convenient for treating osteoporosis and for minimizing adverse gastrointestinal effects, particularly adverse esophageal effects. This method is also useful for improving patient acceptance and compliance.

Prevention of osteoporosis.

Alendronate tablets or liquid formulations containing about 70 mg of alendronate, on an alendronic acid active basis, are prepared (see EXAMPLES 7 and The tablets or liquid formulations are orally administered to a human patient biweekly, i.e. preferably about once every fourteen days (for example, on alternate Sundays), for a period of at least one year. This method of administration is useful and convenient for preventing osteoporosis and for minimizing adverse Sgastrointestinal effects, particularly adverse esophageal effects. This method is also useful for improving patient acceptance and compliance.

O

00 EXAMPLE 00 Twice-monthly dosing regimen.

Treatment of osteoporosis.

Cl Alendronate tablets or liquid formulations containing about 140 mg of S 10 alendronate, on an alendronic acid active basis, are prepared (see EXAMPLES 7 and S8). The tablets or liquid formulations are orally administered to a human twicemonthly, i.e. preferably about once every fourteen to sixteen days (for example, on about the first and fifteenth of each month), for a period of at least one year. This method of administration is useful and convenient for treating Osteoporosis and for minimizing adverse gastrointestinal effects, particularly adverse esophageal effects.

This method is also useful for improving patient acceptance and compliance.

Prevention of osteoporosis.

Alendronate tablets or liquid formulations containing about 70 mg of alendronate, on an alendronic acid active basis, are prepared (see EXAMPLES 7 and The tablets or liquid formulations are orally administered to a human patient biweekly, i.e. preferably once every fourteen to sixteen days (for example, on about the first and fifteenth of each month), for a period of at least one year. This method of administration is useful and convenient for preventing osteoporosis and for minimizing adverse gastrointestinal effects, particularly adverse esophageal effects.

This method is also useful for improving patient acceptance and compliance.

EXAMPLE 6 In further embodiments, alendronate tablets or liquid formulations are orally dosed, at the desired dosage, according to the dosing schedules of EXAMPLES for treating or preventing other disorders associated with abnormal bone resorption.

In yet further embodiments, other bisphosphonate compounds are orally dosed, at the desired dosage, according to the dosing schedules of EXAMPLES for treating or preventing osteoporosis or for treating or preventing other Sconditions associated with abnormal bone resorption.

O

00 EXAMPLE 7 Bisphosphonate tablets.

00 Bisphosphonate containing tablets are prepared using standard rnixinc Sand formation techniques as described in U.S. Patent No. 5,358,94 1, to Bechard ct al., m 10 issued October 25, 1994, which is incorporated by reference herein in its entirety.

Tablets containing about 35 mg of alendronate, on an alendronic acid active basis, are prepared using the following relative weights of ingredients.

Ingredient Per Tablet Per 4000 Tablets Alendronate Monosodium Trihydrate 45.68 mg 182.72 g Anhydrous Lactose, NF 71.32 mg 285.28 g Microcrystalline Cellulose, NF 80.0 mg 320.0 g Magnesium Stearate, NF 1.0 mg 4.0 g Croscarmellose Sodium, NF 2.0 mg 8.0 g The resulting tablets are useful for administration in accordance with the methods of the present invention for inhibiting bone resorption.

Similarly, tablets comprising other relative weights of alendronate, on an alendronic acid active basis are prepared: about 8.75, 17.5, 70, and 140 mg per tablet. Also, tablets containing other bisphosphonates at appropriate active levels are similarly prepared: cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, and pharmaceutically acceptable salts thereof. Also, tablets containing combinations of bisphosphonates are similarly prepared.

EXAMPLE 8 Liquid Bisphosphonate Formulation.

SLiquid bisphosphonate formulations arc prepared using standard O mixing techniques.

00 A liquid formulation containing about 70 mg of alendronate monosodium trihydrate, on an alendronic acid active basis, per about 75 mL of liquid is prepared using thie following relative weights of ingredients.

Inoredient Weight Alendronate Monosodium Trihydrate 91.35 mg Sodium Propylparaben 22.5 mg Sodium Butylparaben 7.5 mg Sodium Citrate Dihydrate 1500 mg Citric Acid Anhydrous 56.25 mo Sodium Saccharin 7.5 mg Water qs 75 mL 1 N Sodium Hydroxide (aq) qs pH 6.75 The resulting liquid formulation is useful for administration as a unit dosage in accordance with the methods of the present invention for inhibiting bone resorption.

Similarly, liquid formulations comprising other relative weights of alendronate, on an alendronic acid active basis, per unit dosage are prepared: e.g., about 8.75, 17.5, 35, and 140 mg per 75 mL volume. Also, the liquid formulations are prepared to provide other volumes for the unit dosage, e.g. about 135 mL. Also, the liquid formulations are prepared containing other bisphosphonates at appropriate active levels: cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, and pharmaceutically acceptable salts thereof. Also, liquid formulations containing combinations of bisphosphonates are similarly prepared.

Claims (276)

1. A method for inhibiting bone rcsorption in a mammal, said method O comprising orally administering to said mammal a pharmaceutically effective amount of a bisphosphonate selected from the group consisting of alendronate, ibandronate, risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof 00 as a unit dosage-according to a continuous schedule having a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twicc-monthly dosing. tt")

2. A method according to Claim I whercin said mnammal is a hum;in.

3. A method according to Claim 2 wherein said dosine interval is once-weekly.

4. A method according to Claim 3 wherein said unit dosage of said bisphosphonate comprises from about 3.5 mg to about 200 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. A method according to Claim 3 wherein said unit dosage of said bisphosphonate comprises from about 3.5 mg to about 200 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

6. A method according to Claim 5 wherein said pharmaceutically acceptable salt is risedronate monosodium hemi-pentahydrate.

7. A pharmaceutical composition comprising about 35 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

8. A pharmaceutical composition comprising about 40 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. -31- S9. A pharmaceutical composition comprising about 45 mg, on an o acid active basis, of a bisphosphonate selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. N A pharmaceutical composition comprising about 50 mg, on an 00 acid active basis, of a bisphosphonate selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. I 10 11. A pharmaceutical composition comprising about 35 mg, on an O acid active basis, of a bisphosphonate selected from the group consisting of C risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

12. A pharmaceutical composition comprising about 40 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

13. A pharmaceutical composition comprising about 45 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

14. A pharmaceutical composition comprising about 50 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. A pharmaceutical composition according to any of claims 11-14 wherein said pharmaceutically acceptable salt is risedronate monosodium hemi- pentahydrate

16. A kit for inhibiting bone resorption in a mammal, said kit comprising at least one pharmaceutically effective unit dosage of a bisphosphonate selected from the group consisting of alendronate, ibandronate, risedronate, pharmaceutically acceptable salts or ester thereof, and mixtures thereof, for oral administration according to a continuous schedule having a dosing interval selected -32- 0 from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly Sdosing, and twice-monthly dosing. 00 0 -I O1 1O The claims defining the invention are as follows: 1. A method for inhibiting bone resorption in a mammal, said method comprising orally Sadministering to said mammal a pharmaceutically effective amount of a bisphosphonate as a unit O dosage alone or in combination with a unit dosage of a histamine H2 receptor blocker or a proton 00 pump inhibitor according to a continuous schedule having a periodicity from about once every 3 days to about once every 16 days. 2. A bisphosphonate alone or in combination with a histamine H2 receptor blocker or a oO proton pump inhibitor when used orally in inhibiting bone resorption according to a continuous schedule having a periodicity from about once every 3 days to about once every 16 days. C 3. The use of a bisphosphonate alone or in combination with a histamine H2 receptor blocker or a proton pump inhibitor for the manufacture of a unit dosage or unit dosages for oral 0administration according to a continuous schedule having a periodicity from about once every 3 days to about once every 16 days for inhibiting bone resorption. 4. A method, bisphosphonate or combination when used, or use according to any one of .1 claims 1 to 3, wherein the continuous schedule has a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice-monthly dosing. A method, bisphosphonate or combination when used, or use according to any one of claims 1 to 4, wherein said bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. 6. A method, bisphosphonate or combination when used, or use according to claim wherein said bisphosphonate is selected from the group consisting of alendronate, ibandronate, risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. 7. A method, bisphosphonate or combination when used, or use according to claim 6, wherein said bisphosphonate is selected from the group consisting of alendronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. 8. A method, bisphosphonate or combination when used, or use according to claim 7, wherein said bisphosphonate is a pharmaceutically acceptable salt of alendronate, said pharmaceutically acceptable salt being selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts. 9. A method, bisphosphonate or combination when used, or use according to claim 8, wherein said pharmaceutically acceptable salt is a sodium salt. A method, bisphosphonate or combination when used, or use according to claim 9, wherein said pharmaceutically acceptable salt is a monosodium salt. 11. A method, bisphosphonate or combination when used, or use according to any one of claims 1 to 9, wherein said alendronate, acid, ester or pharmaceutically acceptable salt is hydrated. 12. A method, bisphosphonate or combination when used, or use according to claim wherein said pharmaceutically acceptable salt is alendronate monosodium trihydrate. (R:\LIBAj4341doc:mef O 13. A method, bisphosphonate or combination when used, or use according to any one of CN claims 7 to 12, wherein said unit dosage of said bisphosphonate comprises from about 8.75 to about 140mg on an alendronic acid active basis. O 14. A method, bisphosphonate or combination when used, or use according to any one of claims 1 to 13, wherein said dosing interval is once-weekly. A method, bisphosphonate or combination when used, or use according to claim 14, O wherein said unit dosage of said bisphosphonate comprises from about 17.5mg to about 70mg of alendronate monosodium trihydrate, on an alendronic acid active basis. 16. A method, bisphosphonate or combination when used, or use according to claim C ,o wherein said unit dosage of said bisphosphonate comprises about 35mg on an alendronic acid active basis.

17. A method, bisphosphonate or combination when used, or use according to claim wherein said unit dosage of said bisphosphonate comprises about 70mg of alendronate monosodium trihydrate, on an alendronic acid active basis. i 18. A method, bisphosphonate or combination when used, or use according to any one of claims 1 to 13, wherein said dosing interval is twice-weekly.

19. A method, bisphosphonate or combination when used, or use according to claim 18, wherein said unit dosage of said bisphosphonate comprises from about 8.75mg to about 35mg of alendronate monosodium trihydrate, on an alendronic acid active basis.

20. A method, bisphosphonate or combination when used, or use according to any one of claims 1 to 13, wherein said dosing interval is biweekly.

21. A method, bisphosphonate or combination when used, or use according to claim wherein said unit dosage of said bisphosphonate comprises from about 35mg to about 140mg of alendronate monosodium trihydrate, on an alendronic acid active basis.

22. A method, bisphosphonate or combination when used, or use according to any one of claims 1 to 13, wherein said dosing interval is twice-monthly.

23. A method, bisphosphonate or combination when used, or use according to claim 22, wherein said unit dosage of said bisphosphonate comprises about 35mg to about 140mg of alendronate monosodium trihydrate, on an alendronic acid active basis.

24. A method, bisphosphonate or combination when used, or use according to claim 6, wherein said bisphosphonate is selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. A method, bisphosphonate or combination when used, or use according to claim 24, wherein said pharmaceutically acceptable salt is risedronate monosodium hemi-pentahydrate.

26. A method, bisphosphonate or combination when used, or use according to claim 24 or claim 25, wherein said unit dosage of said bisphosphonate comprises from about 3.5mg to about 200mg, on an acid active basis.

27. A method, bisphosphonate or combination when used, or use according to claim 26, wherein said unit dosage of said bisphosphonate comprises about 35 mg on an acid active basis. [R:\LIBA]4341.do:mcf o 28. A method, bisphosphonate or combination when used, or use according-to claim 26, 1 wherein said unit dosage of said bisphosphonate comprises about 40 mg on an acid active basis. o 29. A method, bisphosphonate or combination when used, or use according to claim 26, O wherein said unit dosage of said bisphosphonate comprises about 45 mg on an acid active basis. oo

30. A method, bisphosphonate or combination when used, or use according to claim 26, wherein said unit dosage of said bisphosphonate comprises about 50 mg on an acid active basis. 0o 31. A method, bisphosphonate or combination when used, or use according to claim 6, wherein said bisphosphonate is selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. N to 32. A method, bisphosphonate or combination when used, or use according to claim 31, 0wherein said unit dosage of said bisphosphonate comprises from about 3.5mg to about 200mg, on San acid active basis.

33. A method, bisphosphonate or combination when used, or use according to claim 32, wherein said unit dosage of said bisphosphonate comprises about 35 mg on an acid active basis.

34. A method, bisphosphonate or combination when used, or use according to claim 32, wherein said unit dosage of said bisphosphonate comprises about 40 mg on an acid active basis. A method, bisphosphonate or combination when used, or use according to claim 32, wherein said unit dosage of said bisphosphonate comprises about 45 mg on an acid active basis.

36. A method, bisphosphonate or combination when used, or use according to claim 32, wherein said unit dosage of said bisphosphonate comprises about 50 mg on an acid active basis.

37. A method, bisphosphonate or combination when used, or use according to any one of claims 1 to 12, 24, 25 or 31, wherein said unit dosage of said bisphosphonate comprises from about 1.5 to about 6000pIg/kg body weight.

38. A method, bisphosphonate or combination when used, or use according to any one of claims 1 to 12, 24, 25 or 31, wherein said unit dosage of said bisphosphonate comprises from about 10 to about 2000pig/kg body weight.

39. A method, bisphosphonate or combination when used, or use according to any one of claims 1 to 38, wherein said histamine H2 receptor blocker or said proton pump inhibitor is administered from about 30 minutes to about 24 hours prior to the administration of said bisphosphonate. A method, bisphosphonate or combination when used, or use according to any one of claims 1 to 39, wherein said histamine H2 receptor blocker or proton pump inhibitor is selected from the group consisting of cimetidine, famotidine, nizatidine, ranitidine, omeprazole, and lansoprazole.

41. A method, bisphosphonate or combination when used, or use according to any one of claims 1 to 40, wherein said medicament is in the form of a tablet.

42. A method, bisphosphonate or combination when used, or use according to any one of claims 1 to 40, wherein said medicament is in the form of a capsule.

43. A method, bisphosphonate or combination when used, or use according to any one of claims 1 to 40, wherein said medicament is in the form of a liquid. [R:\LIBA4341 .doc:rnef O 44. A method, bisphosphonate or combination when used, or use according to any one of N claims 1 to 40, wherein said mammal is a human. A method for treating osteoporosis in a mammal, said method comprising orally O administering to said mammal a pharmaceutically effective amount of a bisphosphonate as a unit 0 0 dosage alone or in combination with a unit dosage of a histamine H2 receptor blocker or a proton pump inhibitor ac ording to a continuous schedule having a periodicity from about once every 3 o0 days to about once every 16 days.

46. A bisphosphonate alone or in combination with a histamine H2 receptor blocker or a proton pump inhibitor when used orally in treating osteoporosis according to a continuous schedule Siu having a periodicity from about once every 3 days to about once every 16 days.

47. The use of a bisphosphonate alone or in combination with a histamine H2 receptor Sblocker or a proton pump inhibitor for the manufacture of a unit dosage or unit dosages for oral administration according to a continuous schedule having a periodicity from about once every 3 days to about once every 16 days for treating osteoporosis.

48. A method, bisphosphonate or combination when used, or use according to any one of claims 45 to 47, wherein the continuous schedule has a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice-monthly dosing.

49. A method, bisphosphonate or combination when used, or use according to any one of claims 45 to 48, wherein said bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. A method, bisphosphonate or combination when used, or use according to claim 49, wherein said bisphosphonate is selected from the group consisting of alendronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

51. A method, bisphosphonate or combination when used, or use according to claim wherein said bisphosphonate is a pharmaceutically acceptable salt of alendronate, said pharmaceutically acceptable salt being selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts.

52. A method, bisphosphonate or combination when used, or use according to claim 51, wherein said pharmaceutically acceptable salt is a sodium salt.

53. A method, bisphosphonate or combination when used, or use according to claim 52, wherein said pharmaceutically acceptable salt is a monosodium salt.

54. A method, bisphosphonate or combination when used, or use according to any one of claims 45 to 53, wherein said alendronate, acid, ester, or pharmaceutically acceptable salt is hydrated. A method, bisphosphonate or combination when used, or use according to claim 52, wherein said pharmaceutically acceptable salt is alendronate monosodium trihydrate. [R:\LIBA]4341.doc:mef O 56. A method, bisphosphonate or combination when used, or use according to any one of cN claims 45 to 55, wherein said unit dosage of said bisphosphonate comprises from about 8.75 to about 140mg on an alendronic acid active basis. O 57. A method, bisphosphonate or combination when used, or use according to any one of 00 claims 45 to 56, wherein said dosing interval is once-weekly.

58. A method, bisphosphonate or combination when used, or use according to claim 51, 00 wherein said unit dosage of said bisphosphonate comprises from about 17.5 to about 70mg on an alendronic acid active basis.

59. A method, bisphosphonate or combination when used, or use according to claim 58, (C wherein said unit dosage of said bisphosphonate comprises about 70mg of alendronate monosodium trihydrate, on an alendronic acid active basis. A method, bisphosphonate or combination when used, or use according to any one of claims 45 to 56, wherein said dosing interval is twice-weekly.

61. A method, bisphosphonate or combination when used, or use according to claim wherein said unit dosage of said bisphosphonate comprises about 35mg of alendronate monosodium trihydrate, on an alendronic acid active basis.

62. A method, bisphosphonate or combination when used, or use according to any one of claims 45 to 56, wherein said dosing interval is biweekly.

63. A method, bisphosphonate or combination when used, or use according to claim 62, wherein said unit dosage of said bisphosphonate comprises about 140mg of alendronate monosodium trihydrate, on an alendronic acid active basis.

64. A method, bisphosphonate or combination when used, or use according to any one of claims 45 to 56, wherein said dosing interval is twice-monthly. A method, bisphosphonate or combination when used, or use according to claim 64, wherein said unit dosage of said bisphosphonate comprises about 140mg of alendronate monosodium trihydrate, on an alendronic acid active basis.

66. A method, bisphosphonate or combination when used, or use according to claim 49, wherein said bisphosphonate is selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

67. A method, bisphosphonate or combination when used, or use according to claim 66, wherein said pharmaceutically acceptable salt is risedronate monosodium hemi-pentahydrate.

68. A method, bisphosphonate or combination when used, or use according to claim 66 or claim 67, wherein said unit dosage of said bisphosphonate comprises from about 3.5mg to about 200mg, on an acid active basis.

69. A method, bisphosphonate or combination when used, or use according to claim 68, wherein said unit dosage of said bisphosphonate comprises about 35 mg on an acid active basis. A method, bisphosphonate or combination when used, or use according to claim 68, wherein said unit dosage of said bisphosphonate comprises about 40 mg on an acid active basis. (R:\LIBA4341 .doc:mcf O 71. A method, bisphosphonate or combination when used, or use according to claim 68, c wherein said unit dosage of said bisphosphonate comprises about 45 mg on an acid active basis.

72. A method, bisphosphonate or combination when used, or use according to claim 68, O wherein said unit dosage of said bisphosphonate comprises about 50 mg on an acid active basis. 00 s 73. A method, bisphosphonate or combination when used, or use according to claim 49, wherein said bisphosphonate is selected from the group consisting of ibandronate, o0 pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

74. A method, bisphosphonate or combination when used, or use according to claim 73, wherein said unit dosage of said bisphosphonate comprises from about 3.5mg to about 200mg, on t i an acid active basis. A method, bisphosphonate or combination when used, or use according to claim 74, Swherein said unit dosage of said bisphosphonate comprises about 35 mg on an acid active basis.

76. A method, bisphosphonate or combination when used, or use according to claim 74, wherein said unit dosage of said bisphosphonate comprises about 40 mg on an acid active basis.

77. A method, bisphosphonate or combination when used, or use according to claim 74, wherein said unit dosage of said bisphosphonate comprises about 45 mg on an acid active basis.

78. A method, bisphosphonate or combination when used, or use according to claim 74, wherein said unit dosage of said bisphosphonate comprises about 50 mg on an acid active basis.

79. A method, bisphosphonate or combination when used, or use according to any one of claims 45 to 55, 66, 67 or 73, wherein said unit dosage of said bisphosphonate comprises from about 1.5 to about 6000Vpg/kg body weight. A method, bisphosphonate or combination when used, or use according to any one of claims 45 to 55, 66, 67 or 73, wherein said unit dosage of said bisphosphonate comprises from about 10 to about 2000pg/kg body weight.

81. A method, bisphosphonate or combination when used, or use according to any one of claims 45 to 80, wherein said histamine H2 receptor blocker or said proton pump inhibitor is administered from about 30 minutes to about 24 hours prior to the administration of said bisphosphonate.

82. A method, bisphosphonate or combination when used, or use according to any one of claims 45 to 66, wherein said histamine H2 receptor blocker or proton pump inhibitor is selected from the group consisting of cimetidine, famotidine, nizatidine, ranitidine, omeprazole, and lansoprazole.

83. A method, bisphosphonate or combination when used, or use according to any one of claims 45 to 82, wherein said medicament is in the form of a tablet.

84. A method, bisphosphonate or combination when used, or use according to any one of claims 45 to 82, wherein said medicament is in the form of a capsule. A method, bisphosphonate or combination when used, or use according to any one of claims 45 to 82, wherein said medicament is in the form of a liquid. (R:\LIBA]434 .doc:mef

86. A method, bisphosphonate or combination when used, or use according to any one of N claims 45 to 85, wherein said mammal is a human. 0 87. A method for preventing osteoporosis in a mammal, said method comprising orally O administering to said mammal a pharmaceutically effective amount of a bisphosphonate as a unit 0i 5 dosage alone or in combination with a unit dosage of a histamine H2 receptor blocker or a proton pump inhibitor according to a continuous schedule having a periodicity from about once every 3 oO days to about once every 16 days.

88. A bisphosphonate alone or in combination with a histamine H2 receptor blocker or a proton pump inhibitor when used orally in preventing osteoporosis according to a continuous N 10 schedule having a periodicity from about once every 3 days to about once every 16 days.

89. The use of a bisphosphonate alone or in combination with a histamine H2 receptor blocker or a proton pump inhibitor for the manufacture of a unit dosage or unit dosages for oral administration according to a continuous schedule having a periodicity from about once every 3 days to about once every 16 days for preventing osteoporosis.

90. A method, bisphosphonate or combination when used, or use according to any one of claims 87 to 89, wherein the continuous schedule has a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice-monthly dosing.

91. A method, bisphosphonate or combination when used, or use according to any one of claims 87 to 89, wherein said bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

92. A method, bisphosphonate or combination when used, or use according to claim 91, wherein said bisphosphonate is selected from the group consisting of alendronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

93. A method, bisphosphonate or combination when used, or use according to claim 92, wherein said bisphosphonate is a pharmaceutically acceptable salt of alendronate, said pharmaceutically acceptable salt being selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts.

94. A method, bisphosphonate or combination when used, or use according to claim 92, wherein said pharmaceutically acceptable salt is a sodium salt. A method, bisphosphonate or combination when used, or use according to claim 94, wherein said pharmaceutically acceptable salt is a monosodium salt.

96. A method, bisphosphonate or combination when used, or use according to any one of claims 87 to 95, wherein said alendronate, acid, ester or pharmaceutically acceptable salt is hydrated.

97. A method, bisphosphonate or combination when used, or use according to claim 96, wherein said pharmaceutically acceptable salt is alendronate monosodium trihydrate. [R:\LIBA)4341.doc:mef o 98. A method, bisphosphonate or combination when used, or use according to any one of cN claims 87 to 97, wherein said unit dosage of said bisphosphonate comprises from about 8.75 to about 140mg on an alendronic acid active basis. O 99. A method, bisphosphonate or combination when used, or use according to any one of c 0 5 claims 87 to 98, wherein said dosing interval is once-weekly.

100. A method, bisphosphonate or combination when used, or use according to claim 99, 0O wherein said unit dosage of said bisphosphonate comprises from about 17.5 to about 70mg on an alendronic acid active basis. r- 101. A method, bisphosphonate or combination when used, or use according to claim 100, (-i Ci io wherein said bisphosphonate unit dosage comprises about 35mg of alendronate monosodium trihydrate, on an alendronic acid active basis. S102. A method, bisphosphonate or combination when used, or use according to any one of (-i claims 87 to 98, wherein said dosing interval is twice-weekly.

103. A method, bisphosphonate or combination when used, or use according to claim 102, wherein said bisphosphonate unit dosage comprises about 17.5mg of alendronate monosodium trihydrate, on an alendronic acid active basis.

104. A method, bisphosphonate or combination when used, or use according to any one of claims 87 to 98, wherein said dosing interval is biweekly.

105. A method, bisphosphonate or combination when used, or use according to claim 104, wherein said bisphosphonate unit dosage comprises about 70mg of alendronate monosodium trihydrate, on an alendronic acid active basis.

106. A method, bisphosphonate or combination when used, or use according to any one of claims 87 to 98, wherein said dosing interval is twice-monthly.

107. A method, bisphosphonate or combination when used, or use according to claim 106, wherein said bisphosphonate unit dosage comprises about 70mg of alendronate monosodium trihydrate, on an alendronic acid active basis.

108. A method, bisphosphonate or combination when used, or use according to claim 91, wherein said bisphosphonate is selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

109. A method, bisphosphonate or combination when used, or use according to claim 108, wherein said pharmaceutically acceptable salt is risedronate monosodium hemi-pentahydrate.

110. A method, bisphosphonate or combination when used, or use according to claim 108 or claim 109, wherein said unit dosage of said bisphosphonate comprises from about 3.5mg to about 200mg, on an acid active basis.

111. A method, bisphosphonate or combination when used, or use according to claim 110, wherein said unit dosage of said bisphosphonate comprises about 35 mg on an acid active basis.

112. A method, bisphosphonate or combination when used, or use according to claim 110, wherein said unit dosage of said bisphosphonate comprises about 40 mg on an acid active basis. (R:\LIBA)4341.doc:mef O 113. A method, bisphosphonate or combination when used, or use according to claim 110, N wherein said unit dosage of said bisphosphonate comprises about 45 mg on an acid active basis. o 114. A method, bisphosphonate or combination when used, or use according to claim 110, O wherein said unit dosage of said bisphosphonate comprises about 50 mg on an acid active basis. 0 5 115. A method, bisphosphonate or combination when used, or use according to claim 91, wherein said bisphosphonate is selected from the group consisting of ibandronate, oO pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

116. A method, bisphosphonate or combination when used, or use according to claim 115, r- wherein said unit dosage of said bisphosphonate comprises from about 3.5mg to about 200mg, on cI tu an acid active basis.

117. A method, bisphosphonate or combination when used, or use according to claim 116, Swherein said unit dosage of said bisphosphonate comprises about 35 mg on an acid active basis.

118. A method, bisphosphonate or combination when used, or use according to claim 116, wherein said unit dosage of said bisphosphonate comprises about 40 mg on an acid active basis.

119. A method, bisphosphonate or combination when used, or use according to claim 116, wherein said unit dosage of said bisphosphonate comprises about 45 mg on an acid active basis.

120. A method, bisphosphonate or combination when used, or use according to claim 116, wherein said unit dosage of said bisphosphonate comprises about 50 mg on an acid active basis.

121. A method, bisphosphonate or combination when used, or use according to any one of claims 87 to 97, 108, 109 or 115, wherein said unit dosage of said bisphosphonate comprises from about 1.5 to about 6000pg/kg body weight.

122. A method, bisphosphonate or combination when used, or use according to any one of claims 87 to 97, 108, 109 or 115, wherein said unit dosage of said bisphosphonate comprises from about 10 to about 2000,ug/kg body weight.

123. A method, bisphosphonate or combination when used, or use according to any one of claims 87 to 122, wherein said histamine H2 receptor blocker or said proton pump inhibitor is administered from about 30 minutes to about 24 hours prior to the administration of said bisphosphonate.

124. A method, bisphosphonate or combination when used, or use according to any one of claims 87 to 123, wherein said histamine H2 receptor blocker or proton pump inhibitor is selected from the group consisting of cimetidine, famotidine, nizatidine, ranitidine, omeprazole, and lansoprazole.

125. A method, bisphosphonate or combination when used, or use according to any one of claims 87 to 124, wherein said medicament is in the form of a tablet.

126. A method, bisphosphonate or combination when used, or use according to any one of claims 87 to 124, wherein said medicament is in the form of a capsule.

127. A method, bisphosphonate or combination when used, or use according to any one of claims 87 to 124, wherein said medicament is in the form of a liquid. [R\LIBA]4341.doc:ncf O 128. A method, bisphosphonate or combination when used, or use according to any one of c- claims 87 to 124, wherein said mammal is a human. ,o 129. A kit comprising at least one pharmaceutically effective unit dosage of a O bisphosphonate for oral administration in conjunction with administration instructions defining a 00 continuous schedule having a periodicity from about once every 3 days to about once every 16 days, when used for inhibiting bone resorption or for treating or preventing osteoporosis. 00 130. A kit comprising at least one pharmaceutically effective unit dosage of a bisphosphonate for oral administration in conjunction with administration instructions defining a r- continuous schedule having a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice-monthly dosing, when used for inhibiting bone resorption or for treating or preventing osteoporosis. S131. A kit according to claim 130, wherein said dosing interval is once-weekly.

132. A kit according to any one of claims 129 to 131, wherein said bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, pharmaceutically acceptable salts thereof, and mixtures thereof.

133. A kit according to claim 132, wherein said bisphosphonate is selected from the group consisting of alendronate, ibandronate, risedronate, pharmaceutically acceptable salts thereof, and mixtures thereof.

134. A kit according to claim 133, wherein said bisphosphonate is selected from the group consisting of alendronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

135. A kit according to claim 134, wherein said bisphosphonate is a pharmaceutically acceptable salt of alendronate, said pharmaceutically acceptable being selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts.

136. A kit according to claim 135, wherein said pharmaceutically acceptable salt is a sodium salt.

137. A kit according to claim 136, wherein said pharmaceutically acceptable salt is a monosodium salt.

138. A kit according to any one of claims 129-137, wherein said alendronate, acid, ester or pharmaceutically acceptable salt is hydrated.

139. A kit according to claim 138, wherein said pharmaceutically acceptable salt is alendronate monosodium trihydrate.

140. A kit according to any one of claims 134 to 139, wherein said unit dosage of said bisphosphonate comprises from about 8.75 to about 140mg on an alendronic acid active basis.

141. A kit according to claim 140, wherein said unit dosage of said bisphosphonate comprises from about 17.5 to about 70mg on an alendronic acid active basis.

142. A kit according to claim 141, wherein said unit dosage of said bisphosphonate comprises about 35mg on an alendronic acid active basis. [R:\LIBA]434 .doc:mcf

143. A kit according to claim 141, wherein said unit dosage of said bisphosphonate comprises about 70mg on an alendronic acid active basis.

144. A kit according to claim 133, wherein said bisphosphonate is selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

145. A kit according to claim 144, wherein said pharmaceutically acceptable salt is risedronate monosodium hemi-pentahydrate.

146. A kit according to claim 144 or claim 145, wherein said unit dosage of said bisphosphonate comprises from about 3.5mg to about 200mg, on an acid active basis.

147. A kit according to claim 146, wherein o1 comprises about 35 mg on an acid active basis.

148. A kit according to claim 146, wherein comprises about 40 mg on an acid active basis.

149. A kit according to claim 146, wherein comprises about 45 mg on an acid active basis.

150. A kit according to claim 146, wherein comprises about 50 mg on an acid active basis. said unit dosage of said bisphosphonate said unit dosage of said bisphosphonate said unit dosage of said bisphosphonate said unit dosage of said bisphosphonate

151. A kit according to claim 133, wherein said bisphosphonate is selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

152. A kit according to claim 151, wherein said unit dosage comprises from about 3.5mg to about 200mg, on an acid active basis. of said bisphosphonate

153. A kit according to claim 152, wherein comprises about 35 mg on an acid active basis.

154. A kit according to claim 152, wherein comprises about 40 mg on an acid active basis.

155. A kit according to claim 152, wherein comprises about 45 mg on an acid active basis.

156. A kit according to claim 152, wherein comprises about 50 mg on an acid active basis. said unit dosage of said bisphosphonate said unit dosage of said bisphosphonate said unit dosage of said bisphosphonate said unit dosage of said bisphosphonate

157. A kit according to any one of claims 129 to 139, 144, 145 or 151, wherein said unit dosage of said bisphosphonate comprises from about 1.5 to about 6000ptg/kg body weight.

158. A kit according to any one of claims 129 to 139, 144, 145 or 151, wherein said unit dosage of said bisphosphonate comprises from about 10 to about 2000pg/kg body weight.

159. A kit according to any one of claims 129 to 158, wherein said kit further comprises a memory aid for administering said unit dosages.

160. A kit according to any one of claims 129 to 159, wherein said unit dosages are oriented in said pharmaceutical kit in the order of their intended use.

161. A kit according to claim 159 or claim 160, wherein said memory aid indicates a unit dosage is administered on each of week 1, week 2, week 3, and week 4. [R:\LIBA)4341.doc:mcf o 162. A kit according to claim 160 or claim 161, wherein said memory aid indicates that said C1 unit dosage is administered once during a seven day period. 0 163. A kit according to any one of claims 129 to 162, wherein said unit dosage is in the O form of a tablet. 0O 164. A kit according to any one of claims 129 to 162, wherein said unit dosage is in the form of a capsule. oO 165. A kit according to any one of claims 129 to 162, wherein said unit dosage is in the form of a liquid.

166. A kit comprising: C 1 at least one pharmaceutically effective unit dosage of a bisphosphonate for oral administration, and S(b) at least one pharmaceutically effective unit dosage of a histamine H2 receptor blocker or a proton pump inhibitor when used for inhibiting bone resorption or for treating or preventing osteoporosis.

167. A kit according to claim 166, wherein said bisphosphonate is selected from the group consisting of alendronate, cimadronat6, clodronate, tiludronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

168. A kit according to claim 167, wherein said bisphosphonate is selected from the group consisting of alendronate, ibandronate, risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

169. A kit according to any one of claims 166 to 168, wherein said histamine H2 receptor blocker or proton pump inhibitor is selected from the group consisting of cimetidine, famotidine, nizatidine, ranitidine, omeprazole, and lansoprazole.

170. A pharmaceutical kit when used for inhibiting bone resorption in a mammal comprising at least one pharmaceutically effective unit dosage of a bisphosphonate for oral administration according to a continuous schedule characterised in that said unit dosage of said bisphosphonate comprises about 70mg, on an alendronic acid active basis, of a bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof, said continuous schedule is once-weekly, and said kit comprises a memory aid for administering said unit dosages.

171. A pharmaceutical kit according to claim 170, wherein said unit dosages are oriented in said pharmaceutical kit in the order of their intended use.

172. A pharmaceutical kit according to claim 171, wherein said memory aid indicates that said unit dosage is administered once a week.

173. A pharmaceutical kit according to claim 172, wherein said memory aid indicates a unit dosage is administered on each of week 1, week 2, week 3, and week 4. [R:\LIBA)4341.doc:mef O 174. A pharmaceutical kit according to claim 173, wherein said memory aid indicates that Nc said unit dosage is administered once during a seven day period. o 175. Use of a kit comprising at least one pharmaceutically effective unit dosage of a O bisphosphonate for oral administration in conjunction with administration instructions defining a o 0 5 continuous schedule having a periodicity from about once every 3 days to about once every 16 days for inhibiting bone resorption or for treating or preventing osteoporosis. 00 176. Use of a kit comprising at least one pharmaceutically effective unit dosage of a bisphosphonate for oral administration in conjunction with administration instructions defining a continuous schedule having a dosing interval selected from the group consisting of once-weekly (c 1o dosing, twice-weekly dosing, biweekly dosing, and twice-monthly dosing for inhibiting bone Sresorption or for treating or preventing osteoporosis. S177. Use according to claim 176, wherein said dosing interval is once-weekly.

178. Use according to any one of claims 175 to 177, wherein said bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, pharmaceutically acceptable salts thereof, and mixtures thereof.

179. Use according to claim 178, wherein said bisphosphonate is selected from the group consisting of alendronate, ibandronate, risedronate, pharmaceutically acceptable salts thereof, and mixtures thereof.

180. Use according to claim 179, wherein said bisphosphonate is selected from the group consisting of alendronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

181. Use according to claim 180, wherein said bisphosphonate is a pharmaceutically acceptable. salt of alendronate, said pharmaceutically acceptable being selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts.

182. Use according to claim 181, wherein said pharmaceutically acceptable salt is a sodium salt.

183. Use according to claim 182 wherein said pharmaceutically acceptable salt is a monosodium salt.

184. Use according to any of claims 175 to 183, wherein said alendronate, acid, ester or pharmaceutically acceptable salt is hydrated.

185. Use according to claim 184, wherein said pharmaceutically acceptable salt is alendronate monosodium trihydrate.

186. Use according to any one of claims 181 to 185, wherein said unit dosage of said bisphosphonate comprises from about 8.75 to about 140mg on an alendronic acid active basis.

187. Use according to claim 186, wherein said unit dosage of said bisphosphonate comprises from about 17.5 to about 70mg on an alendronic acid active basis.

188. Use according to claim 187, wherein said unit dosage of said bisphosphonate comprises about 35mg on an alendronic acid active basis. [R:\LIBAj4341.doc:mcf

189. Use according to claim 186, wherein said unit dosage of said bisphosphonate comprises about 70mg on an alendronic acid active basis.

190. Use according to claim 178, wherein said bisphosphonate is selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

191. A use according to claim 190, wherein said pharmaceutically acceptable salt is risedronate monosodium hemi-pentahydrate.

192. Use according to claim 190 or claim 191, wherein said unit dosage of said bisphosphonate comprises from about 3.5mg to about 200mg, on an acid active basis.

193. Use according to claim 192, wherein o1 comprises about 35 mg on an acid active basis.

194. Use according to claim 192, wherein comprises about 40 mg on an acid active basis.

195. Use according to claim 192, wherein comprises about 45 mg on an acid active basis.

196. Use according to claim 192, wherein comprises about 50 mg on an acid active basis. said unit dosage of said bisphosphonate said unit dosage of said bisphosphonate said unit dosage of said bisphosphonate said unit dosage of said bisphosphonate

197. Use according to claim 178, wherein said bisphosphonate is selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

198. Use according to claim 197, wherein said unit dosage comprises from about 3.5mg to about 200mg, on an acid active basis.

199. Use according to claim 198, wherein said unit dosage comprises about 35 mg on an acid active basis.

200. Use according to claim 198, wherein said unit dosage comprises about 40 mg on an acid active basis.

201. Use according to claim 198, wherein said unit dosage comprises about 45 mg on an acid active basis.

202. Use according to claim 198, wherein said unit dosage comprises about 50 mg on an acid active basis. of said bisphosphonate of said bisphosphonate of said bisphosphonate of said bisphosphonate of said bisphosphonate

203. Use according to any one of claims 175 to 185, 190, 191 or 197, wherein said unit dosage of said bisphosphonate comprises from about 1.5 to about 6000igg/kg body weight.

204. Use according to any one of claims 175 to 185, 190, 191 or 197, wherein said unit dosage of said bisphosphonate comprises from about 10 to about 2000pig/kg body weight.

205. Use according to any one of claims 175 to 204, wherein said kit further comprises a memory aid for administering said unit dosages.

206. Use according to any one of claims 175 to 205, wherein said unit dosages are oriented in said pharmaceutical kit in the order of their intended use.

207. Use according to claim 205 or claim 206, wherein said memory aid indicates a unit dosage is administered on each of week 1, week 2, week 3, and week 4. [R:\LIBA)434 I.doc:mcf 0 208. Use according to claim 205 or claim 206, wherein said memory aid indicates that said CN unit dosage is administered once during a seven day period. 0 209. Use according to any one of claims 175 to 208, wherein said unit dosage is in the form O of a tablet.

210. Use according to any one of claims 175 to 208, wherein said unit dosage is in the form of a capsule. oO 211. Use according to any one of claims 175 to 208, wherein said unit dosage is in the form of a liquid.

212. Use of a kit comprising: N 10 at least one pharmaceutically effective unit dosage of a bisphosphonate for oral 0administration, and S(b) at least one pharmaceutically effective unit dosage of a histamine H2 receptor blocker or a proton pump inhibitor for inhibiting bone resorption or for treating or preventing osteoporosis.

213. Use according to claim 212, wherein said bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

214. Use according to claim 213, wherein said bisphosphonate is selected from the group consisting of alendronate, ibandronate, risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

215. Use according to any one of claims 212 to 214, wherein said histamine H2 receptor blocker or proton pump inhibitor is selected from the group consisting of cimetidine, famotidine, nizatidine, ranitidine, omeprazole, and lansoprazole.

216. Use of a pharmaceutical kit for inhibiting bone resorption in a mammal, said kit comprising at least one pharmaceutically effective unit dosage of a bisphosphonate for oral administration according to a continuous schedule characterised in that said unit dosage of said bisphosphonate comprises about 70mg, on an alendronic acid active basis, of a bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof, said continuous schedule is once-weekly, and said kit comprises a memory aid for administering said unit dosages.

217. Use according to claim 216, wherein said unit dosages are oriented in said pharmaceutical kit in the order of their intended use.

218. Use according to claim 217, wherein said memory aid indicates that said unit dosage is administered once a week.

219. Use according to claim 218, wherein said memory aid indicates a unit dosage is administered on each of week 1, week 2, week 3, and week 4. [R:\LIBA4341 .doc:mef 0 220. Use according to claim 219, wherein said memory aid indicates that said unit dosage Sis administered once during a seven day period.

221. A pharmaceutical composition useful for inhibiting bone resorption in a mammal O comprising a pharmaceutically effective amount of a bisphosphonate in association with a 00 5 pharmaceutically acceptable carrier wherein said bisphosphonate is adapted for oral administration as a unit dosage according to a continuous schedule having a periodicity from about once every 3 days to about once every 16 days. 00

222. A pharmaceutical composition useful for inhibiting bone resorption in a mammal comprising a pharmaceutically effective amount of a bisphosphonate in association with a N 1o pharmaceutically acceptable carrier wherein said bisphosphonate is adapted for oral administration as a unit dosage form according to a continuous schedule having a dosing interval selected from 0 the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice- monthly dosing.

223. A pharmaceutical composition according to claim 222, wherein said dosing interval is once-weekly.

224. A pharmaceutical composition according to any one of claims 221 to 223, wherein said bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

225. A pharmaceutical composition according to claim 224, wherein said bisphosphonate is selected from the group consisting of alendronate, ibandronate, risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

226. A pharmaceutical composition according to claim 225, wherein said bisphosphonate is selected from the group consisting of alendronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

227. A pharmaceutical composition according to claim 226, wherein said bisphosphonate is a pharmaceutically acceptable salt of alendronate, said pharmaceutically acceptable salt being selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts.

228. A pharmaceutical composition according to claim 227, wherein said pharmaceutically acceptable salt is a sodium salt.

229. A pharmaceutical composition according to claim 228, wherein said pharmaceutically acceptable salt is a monosodium salt.

230. A pharmaceutical composition according to any one of claims 226 to 229, wherein said alendronate, acid, ester or pharmaceutically acceptable salt is hydrated.

231. A pharmaceutical composition according to claim 230, wherein said pharmaceutically acceptable salt is alendronate monosodium trihydrate. (R:\LIBA]4341.doc:mcf

232. A pharmaceutical composition according to any one of claims 226 to 231, wherein Ssaid unit dosage of said bisphosphonate comprises from about 8.75 to about 140mg on an Salendronic acid active basis. O 233. A pharmaceutical composition according to claim 232, wherein said unit dosage of 00 5 said bisphosphonate comprises from about 17.5 to about 70mg on an alendronic acid active basis.

234. A pharmaceutical composition according to claim 233, wherein said unit dosage of said bisphosphonate comprises about 35mg on an alendronic acid active basis. oO S235. A pharmaceutical composition according to claim 233, wherein said unit dosage of said bisphosphonate comprises about 70mg on an alendronic acid active basis. o 236. A pharmaceutical composition according to claim 225, wherein said bisphosphonate is selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters Sthereof, and mixtures thereof.

237. A pharmaceutical composition according to claim 236, wherein said pharmaceutically acceptable salt is risedronate monosodium hemi-pentahydrate.

238. A pharmaceutical composition according to claim 236 or claim 237, wherein said unit dosage of said bisphosphonate comprises from about 3.5mg to about 200mg, on an acid active basis.

239. A pharmaceutical composition according to claim 238, wherein said unit dosage of said bisphosphonate comprises about 35mg, on an acid active basis.

240. A pharmaceutical composition according to claim 238, wherein said unit dosage of said bisphosphonate comprises about 40 mg, on an acid active basis.

241. A pharmaceutical composition according to claim 238, wherein said unit dosage of said bisphosphonate comprises about 45 mg, on an acid active basis.

242. A pharmaceutical composition according to claim 238, wherein said unit dosage of said bisphosphonate comprises about 50 mg, on an acid active basis.

243. A pharmaceutical composition according to claim 225, wherein said bisphosphonate is selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

244. A pharmaceutical composition according to claim 243 wherein said unit dosage of said bisphosphonate comprises from about 3.5mg to about 200mg, on an acid active basis.

245. A pharmaceutical composition according to claim 244, wherein said unit dosage of said bisphosphonate comprises about 35mg, on an acid active basis.

246. A pharmaceutical composition according to claim 244, wherein said unit dosage of said bisphosphonate comprises about 40 mg, on an acid active basis.

247. A pharmaceutical composition according to claim 244, wherein said unit dosage of said bisphosphonate comprises about 45 mg, on an acid active basis.

248. A pharmaceutical composition according to claim 244, wherein said unit dosage of said bisphosphonate comprises about 50 mg, on an acid active basis. [R:\LIBA)4341.doc:mcf S249. A pharmaceutical composition according to any one of claims 221 to 248, wherein 0 said medicament is in the form of a tablet. S250. A pharmaceutical composition according to any one of claims 221 to 248, wherein O said medicament is in the form of a capsule. o0 5

251. A pharmaceutical composition according to any one of claims 221 to 248, wherein Nsaid medicament is in the form of a liquid.

252. A pharmaceutical composition according to any one of claims 221 to 251, wherein 00 said mammal is a human.

253. A pharmaceutical composition useful for treating osteoporosis in a mammal U in comprising a pharmaceutically effective amount of a bisphosphonate in association with a V) pharmaceutically acceptable carrier wherein said bisphosphonate is adapted for oral administration 0as a unit dosage according to a continuous schedule having a periodicity from about once every 3 days to about once every 16 days.

254. A pharmaceutical composition useful for treating osteoporosis in a mammal comprising a pharmaceutically effective amount of a bisphosphonate in association with a pharmaceutically acceptable carrier wherein said bisphosphonate is adapted for oral administration as a unit dosage form according to a continuous schedule having a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice- monthly dosing.

255. A pharmaceutical composition according to claim 254, wherein said dosing interval is. once-weekly.

256. A pharmaceutical composition according to any one of claims 253 to 255, wherein said bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, pharmaceutically acceptable salts thereof, and mixtures thereof.

257. A pharmaceutical composition according to claim 256, wherein said bisphosphonate is selected from the group consisting of alendronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

258. A pharmaceutical composition according to claim 257, wherein said bisphosphonate is a pharmaceutically acceptable salt of alendronate, said pharmaceutically acceptable salt being selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts.

259. A pharmaceutical composition according to claim 258, wherein said pharmaceutically acceptable salt is a sodium salt.

260. A pharmaceutical composition according to claim 259, wherein said pharmaceutically acceptable salt is a monosodium salt.

261. A pharmaceutical composition according to any one of claims 257 to 260, wherein said alendronate, acid, ester or pharmaceutically acceptable salt is hydrated. [R:\LIBA]4341.doc:mcf

262. A pharmaceutical composition according to claim 261, wherein said pharmaceutically Sacceptable salt is alendronate monosodium trihydrate. S263. A pharmaceutical composition according to any one of claims 253 to 262, wherein O said unit dosage of said bisphosphonate comprises from about 8.75 to about 140mg on an 00 5 alendronic acid active basis. N264. A pharmaceutical composition according to claim 263, wherein said unit dosage of said bisphosphonate comprises from about 17.5 to about 70mg on an alendronic acid active basis. oO

265. A pharmaceutical composition according to claim 264, wherein said unit dosage of said bisphosphonate comprises about 70mg on an alendronic acid active basis. S 10 266. A pharmaceutical composition according to claim 256, wherein said bisphosphonate is In selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters Sthereof, and mixtures thereof.

267. A pharmaceutical composition according to claim 266, wherein said pharmaceutically acceptable salt is risedronate monosodium hemi-pentahydrate.

268. A pharmaceutical composition according to claim 266 or claim 267, wherein said unit dosage of said bisphosphonate comprises from about 3.5mg to about 200mg, on an acid active basis.

269. A pharmaceutical composition according to claim 268, wherein said unit dosage of said bisphosphonate comprises about 35 mg on an acid active basis.

270. A pharmaceutical composition according to claim 268, wherein said unit dosage of said bisphosphonate comprises about 40 mg on an acid active basis.

271. A pharmaceutical composition according to claim 268, wherein said unit dosage of said bisphosphonate comprises about 45 mg on an acid active basis.

272. A pharmaceutical composition according to claim 268, wherein said unit dosage of said bisphosphonate comprises about 50 mg on an acid active basis.

273. A pharmaceutical composition according to claim 256, wherein said bisphosphonate is selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

274. A pharmaceutical composition according to claim 273 wherein said unit dosage of said bisphosphonate comprises from about 3.5mg to about 200mg, on an acid active basis.

275. A pharmaceutical composition according to claim 274, wherein said unit dosage of said bisphosphonate comprises about 35 mg on an acid active basis.

276. A pharmaceutical composition according to claim 274, wherein said unit dosage of said bisphosphonate comprises about 40 mg on an acid active basis.

277. A pharmaceutical composition according to claim 274, wherein said unit dosage of said bisphosphonate comprises about 45 mg on an acid active basis.

278. A pharmaceutical composition according to claim 274, wherein said unit dosage of said bisphosphonate comprises about 50 mg on an acid active basis. (R:\LIBA)4341.doc:mef 53 S279. A pharmaceutical composition according to any one of claims 253 to 278, wherein Ssaid pharmaceutical composition is in the form of a tablet.

280. A pharmaceutical composition according to any one of claims 253 to 278, wherein O said pharmaceutical composition is in the form of a capsule. 00 5 281. A pharmaceutical composition according to any one of claims 253 to 278, wherein said pharmaceutical composition is in the form of a liquid.

282. A pharmaceutical composition according to any one of claims 253 to 281, wherein O Ssaid mammal is a human.

283. A pharmaceutical composition useful for preventing osteoporosis in a mammal tc io comprising a pharmaceutically effective amount of a bisphosphonate in association with a Ipharmaceutically acceptable carrier wherein said bisphosphonate is adapted for oral administration as a unit dosage according to a continuous schedule having a periodicity from about once every 3 days to about once every 16 days.

284. A pharmaceutical composition useful for preventing osteoporosis in a mammal comprising a pharmaceutically effective amount of a bisphosphonate in association with a pharmaceutically acceptable carrier wherein said bisphosphonate is adapted for oral administration as a unit dosage form according to a continuous schedule having a dosing interval selected from the group consisting of once-weekly dosing, twice-weekly dosing, biweekly dosing, and twice- monthly dosing.

285. A pharmaceutical composition according to claim 284, wherein said dosing interval is once-weekly.

286. A pharmaceutical composition according to any one of claims 283 to 285, wherein said bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zoledronate, pharmaceutically acceptable salts thereof, and mixtures thereof.

287. A pharmaceutical composition according to claim 286, wherein said bisphosphonate is selected from the group consisting of alendronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

288. A pharmaceutical composition according to claim 287, wherein said bisphosphonate is a pharmaceutically acceptable salt of alendronate, said pharmaceutically acceptable salt being selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts.

289. A pharmaceutical composition according to claim 288, wherein said pharmaceutically acceptable salt is a sodium salt.

290. A pharmaceutical composition according to claim 289, wherein said pharmaceutically acceptable salt is a monosodium salt.

291. A pharmaceutical composition according to any one of claims 287 to 290, wherein said alendronate, acid, ester or pharmaceutically acceptable salt is hydrated. [R:\LIBA)4341 .doc:mcf 0 292. A pharmaceutical composition according to claim 291, wherein said pharmaceutically Sacceptable salt is alendronate monosodium trihydrate.

293. A pharmaceutical composition according to any one of claims 287 to 291, wherein O said unit dosage of said bisphosphonate comprises from about 8.75 to about 140mg on an 00 s alendronic acid active basis.

294. A pharmaceutical composition according to claim 293, wherein said unit dosage of 0 said bisphosphonate comprises from about 17.5 to about 70mg on an alendronic acid active basis.

295. A pharmaceutical composition according to claim 294, wherein said unit dosage of said bisphosphonate comprises about 35mg on an alendronic acid active basis. N0 296. A pharmaceutical composition according to claim 288, wherein said bisphosphonate is selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters 0 thereof, and mixtures thereof.

297. A pharmaceutical composition according to claim 296, wherein said pharmaceutically acceptable salt is risedronate monosodium hemi-pentahydrate.

298. A pharmaceutical composition according to claim 296 or claim 297, wherein said unit dosage of said bisphosphonate comprises from about 3.5mg to about 200mg, on an acid active basis.

299. A pharmaceutical composition according to claim 298, wherein said unit dosage of said bisphosphonate comprises about 35 mg on an acid active basis.

300. A pharmaceutical composition according to claim 298, wherein said unit dosage of said bisphosphonate comprises about 40 mg on an acid active basis.

301. A pharmaceutical composition according to claim 298, wherein said unit dosage of said bisphosphonate comprises about 45 mg on an acid active basis.

302. A pharmaceutical composition according to claim 298, wherein said unit dosage of said bisphosphonate comprises about 50 mg on an acid active basis.

303. A pharmaceutical composition according to claim 286, wherein said bisphosphonate is selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

304. A pharmaceutical composition according to claim 303, wherein said unit dosage of said bisphosphonate comprises from about 3.5mg to about 200mg, on an acid active basis.

305. A pharmaceutical composition according to claim 304, wherein said unit dosage of said bisphosphonate comprises about 35 mg on an acid active basis.

306. A pharmaceutical composition according to claim 304, wherein said unit dosage of said bisphosphonate comprises about 40 mg on an acid active basis.

307. A pharmaceutical composition according to claim 304, wherein said unit dosage of said bisphosphonate comprises about 45 mg on an acid active basis.

308. A pharmaceutical composition according to claim 304, wherein said unit dosage of said bisphosphonate comprises about 50 mg on an acid active basis. [R:\LIBA14341.doc-mef

309. A pharmaceutical composition according to any one of claims 283 to 308, wherein Ssaid pharmaceutical composition is in the form of a tablet. (Ni

310. A pharmaceutical composition according to any one of claims 283 to 308, wherein o O said pharmaceutical composition is in the form of a capsule. 00 oO 311. A pharmaceutical composition according to any one of claims 283 to 308, wherein said pharmaceutical composition is in the form of a liquid.

312. A pharmaceutical composition according to any one of claims 283 to 311, wherein 00 said mammal is a human.

313. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier (-i to in association with about 70 mg, on an alendronic acid basis, of a bisphosphonate selected from in the group consisting of alendronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof wherein said bisphosphonate is adapted for oral administration as a unit dosage according to a continuous schedule having a periodicity of about once-weekly.

314. A pharmaceutical composition according to claim 313, wherein said pharrmaceutically acceptable salt of alendronate is selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts.

315. A pharmaceutical composition according to claim 314, wherein said pharmaceutically acceptable salt is a sodium salt.

316. A pharmaceutical composition according to claim 315, wherein said pharmaceutically acceptable salt is a monosodium salt.

317. A pharmaceutical composition according to any one of claims 313 to 316, wherein said alendronate, acid, ester or pharmaceutically acceptable salt is hydrated.

318. A pharmaceutical composition according to claim 317, wherein said pharmaceutically acceptable salt is alendronate monosodium trihydrate.

319. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier in association with about 35 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof wherein said bisphosphonate is adapted for oral administration as a unit dosage according to a continuous schedule having a periodicity of about once-weekly.

320. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier in association with about 40 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof wherein said bisphosphonate is adapted for oral administration as a unit dosage according to a continuous schedule having a periodicity of about once-weekly.

321. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier in association with about 45 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof wherein said bisphosphonate is adapted for oral administration as a unit dosage according to a continuous schedule having a periodicity of about once-weekly. [R:\LIBA]434 .doc:mnf 0 322. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier N< in association with about 50 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures O thereof wherein said bisphosphonate is adapted for oral administration as a unit dosage according 00 s to a continuous schedule having a periodicity of about once-weekly.

323. A pharmaceutical composition according to any one of claims 319 to 322,-wherein said pharmaceutically acceptable salt is risedronate monosodium hemi-pentahydrate.

324. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier in association with about 35 mg, on an acid active basis, of a bisphosphonate selected from the So group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof wherein said bisphosphonate is adapted for oral administration as a unit dosage according to a continuous schedule having a periodicity of about once-weekly.

325. An oral pharmaceutical composition comprising a pharmaceutically acceptable'carrier in association with about 40 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof wherein said bisphosphonate is adapted for oral administration as a unit dosage according to a continuous schedule having a periodicity of about once-weekly.

326. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier in association with about 45 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof wherein said bisphosphonate is adapted for oral administration as a unit dosage according to a continuous schedule having a periodicity of about once-weekly.

327. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier in association with about 50 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof wherein said bisphosphonate is adapted for oral administration as a unit dosage according to a continuous schedule having a periodicity of about once-weekly.

328. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier in association with about 70mg, on an alendronic acid basis, of a bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

329. A pharmaceutical composition according to claim 328, wherein said pharrmaceutically acceptable salt of alendronate is selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts. 3. 330. A pharmaceutical composition according to claim 329, wherein said pharmaceutically acceptable salt is a sodium salt.

331. A pharmaceutical composition according to claim 330, wherein said pharmaceutically acceptable salt is a monosodium salt. IR:\LIBA)4341.doc:mcf 57

332. A pharmaceutical composition according to any one of claims 328 to 331, wherein Ssaid alendronate, acid, ester or pharmaceutically acceptable salt is hydrated.

333. A pharmaceutical composition according to claim 332, wherein said pharmaceutically 0 acceptable salt is alendronate monosodium trihydrate. o00 334. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier in association with about 35 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures o00 thereof.

335. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier Nn, in association with about 40 mg, on an acid active basis, of a bisphosphonate selected from the In group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

336. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier in association with about 45 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

337. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier in association with about 50 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of risedronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

338. A pharmaceutical composition according to any one of claims 334 to 337, wherein said pharmaceutically acceptable salt is risedronate monosodium hemi-pentahydrate.

339. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier in association with about 35 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

340. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier in association with about 40 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

341. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier in association with about 45 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof.

342. An oral pharmaceutical composition comprising a pharmaceutically acceptable carrier in association with about 50 mg, on an acid active basis, of a bisphosphonate selected from the group consisting of ibandronate, pharmaceutically acceptable salts or esters thereof, and mixtures thereof. (R:\LIBA]434 I.doc:ncf -58- tn S343. A pharmaceutical composition according to any one of claims 313 to 342, wherein said pharmaceutical composition is in the form of a tablet. O 344. A pharmaceutical composition according to any one of claims 313 to 342, 00 wherein said pharmaceutical composition is in the form of a capsule.

345. A pharmaceutical composition according to any one of claims 313 to 342, wherein said pharmaceutical composition is in the form of a liquid. 00

346. An oral pharmaceutical composition, substantially as hereinbefore described r with reference to example 7 or example 8. r Dated 7 September, 2005 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [R:\LIBA]07163.doc:JJP