BG63103B1 - The use of alendronate for osteoporosis prevention - Google Patents

Abstract

The alendronate is an aminobisphosphonate and can be used for the prevention of osteoporosis in women with an early menopause. 7 claims

Description

Technical field

The invention relates to the use of alendronate, an aminobisphosphonate, for the prevention of osteoporosis in postmenopausal women.

BACKGROUND OF THE INVENTION

4-Amino-1-hydroxybutyldiene-1,1-bisphosphonic acid alendronate and its pharmaceutically acceptable salts have been found to be useful in the treatment of osteoporosis. Alendronate is a specific inhibitor of bone resorption. It has a high affinity for bone minerals and is selectively taken up by bone, where it inhibits osteoclastic activity. While alendronate has been shown to be useful for restoring bone loss, there is no indication that alendronate prevents bone loss in otherwise healthy individuals.

Maximum bone mass in women is reached at about 30-35 years of age, after which bone mass is progressively lost throughout the rest of life. The rate of this loss increases during early menopause, especially in places with high trabecular bone content.

The likelihood of a normal woman getting at least one osteoporous fracture during her life is more than 40%. Osteoporous fractures, especially in the thigh, are associated with a significant deterioration in quality of life and high treatment costs. Undoubtedly, the overall costs and soreness associated with all osteoporous fractures far outweigh those of the femoral fracture alone, although accurate estimates are not possible.

Currently, the only approved therapy for the prevention of osteoporosis is estrogen replacement therapy. In addition to preventing bone loss associated with reduced endogenous estrogen production, estrogen administration can help reduce post-menstrual symptoms such as vasomotor instability, vaginal atrophy and improve fat profile with a likely reduction in cardiovascular problems. At the doses usually used to prevent bone loss10 ba, many women lose bone despite the constant treatment. In addition, estrogen treatment is also associated with some serious risks, including endometrial carcinoma, symptomatic gallbladder disease, and possibly an increase in the incidence of breast cancer. Although some of these risks may be reduced by the addition of progestins to the therapeutic course or by an early endometrial biopsy, many women do not take long-term estrogen treatment mainly because of poor tolerability and for safety reasons.

It is desirable to have a remedy that can prevent osteoporosis and which does not carry the risks and likely side effects associated with estrogen.

SUMMARY OF THE INVENTION

The invention relates to a method for the prevention of osteoporosis in women with normal bone density, comprising administering a prophylactically effective amount of alendronate or a pharmaceutically acceptable salt thereof for a sufficient period of time.

Another aspect of the invention is a method of reducing the risk of fracture in women by administering a prophylactically effective amount of alendronate or a pharmaceutically acceptable salt thereof for a sufficient period of time.

Another aspect of the invention is a method for the prevention of osteoporosis in early postmenopausal women, which comprises administering a prophylactically effective amount of alendronate or a pharmaceutically acceptable salt thereof.

In the absence of prophylactic treatment, bone microstructure deteriorates, with bone loss progressing, leading to a decrease in bone strength per unit bone mass. It has been found that the prophylactic administration of alendronate in accordance with the invention preserves normal microstructure and normal bone strength. Thus, another aspect of the invention is a method of maintaining normal bone microstructure and bone strength by administering a prophylactically effective amount of alendronate or a pharmaceutically acceptable salt thereof.

Definitions used in the specification and the preferences include the following terminological expressions:

"Prophylactically effective amount": the amount of alendronate or a pharmaceutically acceptable salt thereof that is sufficient to prevent osteoporosis in women who are not currently suffering from osteoporosis. This amount may or may not be a pharmaceutically acceptable amount, for example sufficient to treat osteoporosis, i.e. to restore bone mass in patients currently suffering from osteoporosis.

"Sufficient period of time": a prolonged period of at least three years, preferably longer.

"Osteoporosis": a condition in which human bone density deviates more than twice the norm for maximum bone mineral density.

"Early postmenopausal": less than five years after menstrual periods have been interrupted in women.

Alendronate can be prepared according to any of the methods described in US Patent Nos. 5,019,651, 4,992,007 and Application US 08/286 151. Pharmaceutically acceptable salts of alendronate include alkali metal salts (e.g., Na, K), alkaline earth metals ( for example Ca), inorganic acid salts such as HCl, and organic acid salts such as citric acid and amino acids. Forms of sodium salts, in particular the form of the trihydrate of the monosodium salt, are preferred. The compounds of the present invention may be administered in oral dosage forms, such as tablets, capsules, each of which includes sustained or sustained release formulations, pills, powders, granules, elixirs, pastes, tinctures, suspensions, syrups, emulsions and zydis. They can also be administered in the intravenous (percussion or infusion), intraperitoneal, subcutaneous or intramuscular form - all the forms known in the pharmaceutical art. An effective but non-toxic amount of the desired compound can be used as a prophylactic for osteoporosis.

The dosage regimen used by the method of the invention is selected according to a number of factors, including the patient's age, weight, sex and medical condition; route of administration, renal and hepatic function of the patient;

and the particular compound or salt thereof used. A specialist doctor or clinician can easily determine and prescribe the effective amount of medication needed to prevent osteoporosis.

The oral dosages of the present invention range from 0.05 mg / kg body weight per day to about 1.0 mg / kg per day. Preferred oral dosages in humans may range from a total daily dose of about 2.5 to 20.0 mg per day during the effective treatment period, and the preferred prophylactic amount is 2.5, 5, 10 mg per day.

Alendronate can be given as a single daily dose or in divided doses. It is desirable to administer the doses without food, preferably 30 minutes to 2 hours before meals, for example breakfast, to ensure proper absorption.

In the methods of the present invention, the active ingredient is typically administered in admixture with suitable pharmaceutical diluents, additives or carriers, referred to generally as "carrier materials", selected appropriately in terms of the form of administration for which they are intended, e.g. oral tablets, capsules, elixirs, syrups and the like in accordance with conventional pharmaceutical practice. For example, for oral administration in the form of tablets or capsules, the active ingredient may be combined with an oral non-toxic pharmaceutically acceptable excipient, such as lactose, starch, sucrose, glucose, methylcellulose, croscarmellose sodium, magnesium stearate, mannitol, sorbitol, other. For oral administration in liquid form, the oral drug components may be combined with an oral non-toxic pharmaceutically acceptable excipient, for example ethanol, glycerol water and the like. In addition, suitable binders, lubricants, disintegrants and colorants and inert substances may be added to the mixture of active ingredients when desired or necessary. Suitable binders may include starch, gelatin, natural sugars such as glucose, anhydroglycose, bulk lactose, betalactose and grain sweeteners, natural and synthetic resins such as acacia, tragacanth and sodium alginate, carboxymethylcellulose, polyethylene glycol, and other. The 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 composition is described in US Patent 5,358,941.

The compounds used in this method can be combined with soluble polymeric compounds as target drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide and the like.

Examples of carrying out the invention

The following examples illustrate the invention without limiting it.

Example 1. The women covered in this study were in good overall health between the ages of 45 and 59 and were randomly selected from the targeted population living in a specific geographical area. Most are in early menopause. Less than 15% of participants do not have manifest osteoporosis,

Treated which is evident from the baseline, and spinal double-beam X-ray densiometry.

Each patient was randomly assigned to receive ether-placebo, low-dose alendronate (ALN 2.5 mg daily), high-dose alendronate (ALN 5 mg daily), or estrogen / progestin (E / P) detected. The estrogen / progestin group (US) received conjugated estrogen PREMARIN® (0.625 mg daily) and medroxyprogesterone acetate PRO VERA® (5 mg daily). taken continuously throughout the calendar month. Outside the US the estrogen / progestin group received micronised 17b-estradiol and norethisterone acetate (Trisequens) in a cyclic mode. All patients taking calcium less than 500 mg daily are advised to increase their calcium intake (either with food or supplement) to this level. The distribution in the group is shown in Table 1. The duration of treatment in each group is given in Table 2.

Table 1.

groups

Group 1 Group 2 GROUP TREATMENT N N TOTAL A Placebo 150 300 450 IN ALN 2.5 mg 150 300 450 P ALN 5 mg 150 300 450 D E / P 150 - 150 TOTAL 600 900 1500

ALN = Alendronate

E / P = Estroain / Progestin

Table 2.

Scheme of treatment

YEAR OF RESEARCH GROUP N 1 and 2 3 in 4 5 in 6 A 150 Placebo Placebo ALN-OD; or placebo * B1 150 ALN 2.5 mg ALN 2.5 mg ALN 2.5 mg B2 150 ALN 2.5 mg ALN 2.5 mg Placebo OT 150 ALN 2.5 mg Placebo C1 150 ALN 5 mg ALN 5 mg ALN 5 mg C2 150 ALN 5 mg ALN 5 mg Placebo NW 150 ALN 5 mg Placebo D 150 E / P E / P

ALN = Alendronate

OD = Optimal dose (either 2.5 mg or 5 mg) * Optional random choice in the placebo group - prolongation of 5 and 6 years

E / P = Estrogen / Progestin

The study was anonymous (for a woman who received either alendronate or placebo) for the first two years, at the end of which the first analysis was performed. The study shall remain anonymous until each patient reaches the end of the four years of the study, when anonymity is discontinued individually for each patient. The test patients were informed only if they received active alendronate treatment or not and, if so, whether they had been treated for two or four years. Patients were not informed of the dose of study drug. Those of the study patients who remained in an anonymous study for the 5th or 6th year and those conducting the analysis remained uninformed about the treatment regimen during the extended period.

Group A subjects (see Table 2) continued to take placebo anonymously for four years. At the end of four years, these women were informed that they had received placebo for 1 to 4 years. They were given the choice to further determine (1: 1) between placebo and alendronate and the “optimal” dose or to leave the study.

Groups B1 and C1 received respectively 2.5 and 5 mg of alendronate for six years. The B2 and C2 groups received 2.5 and 5 mg alendronate for four years, respectively, before switching to placebo for the last two years of the study. Those of the study subjects who remained in the study for the 5th or 6th year were uninformed regarding the prescription of the active drug or placebo for the 5th or 6th year. The B3 and B3 groups received 2.5 and 5 mg alendro20 mg respectively for only two years before switching to placebo for the third and fourth years of the study. They discontinue the study after the fourth year.

The subjects in Group D continue the estrogen / progestin treatment announced for four years and then discontinue treatment after the fourth year. After four years, women receiving 10 alendronate did not develop signs of osteoporosis, determined, for example, by a decrease in bone mineral density, while those taking placebo suffered a loss of bone mineral density. The differences of 15 were calculated statistically.

Claims

Claims (7)

1. A method for the prevention of osteoporosis in early postmenopausal women, characterized in that it comprises administering a prophylactically effective dose of alendronate or a pharmaceutically effective salt thereof. The method of claim 1, wherein the alendronate is taken orally. 3. The method of claim 2, wherein alendronate is administered once daily. The method of claim 3, wherein the alendronate salt is a trihydrate of the monosodium salt. 5. A method according to claim 4, wherein the dose is 2.5 to 20 mg per day. A method according to claim 5, wherein the dose is selected from the group comprising 2.5, 5 and 10 mg daily. 7. A method for the prevention of osteoporosis in early postmenopausal women, characterized in that it comprises administering 2.5 to 20 mg daily of the trihydrate of the alendronate monosodium salt.