EA000677B1 - Method for preventing of osteoporosis - Google Patents

Abstract

1. A method of preventing osteoporosis in early postmenopausal women comprising administering a prophylactically effective dose of alendronate or a pharmaceutically effective salt thereof. 2. A method according to claim 1 wherein the alendronate is administered orally. 3. A method according to claim 2 wherein the alendronate is administered once a day. 4. A method according to claim 3 wherein the salt of alendronate is monosodium salt trihydrate. 5. A method according to claim 4 wherein the dose is 2.5 to 20 mg/day. 6. A method according to claim 5 wherein the dose is selected from the group consisting of 2.5, 5, and 10 mg/day. 7. A method of preventing osteoporosis in early postmenopausal women comprising administering 2.5 to 20 mg/day of alendronate monosodium salt trihydrate during 3 years.

Description

Scope of invention

This invention relates to the use of alendronate, aminodiphosphonate, to prevent osteoporosis in women in early postmenopausal women.

Background to the invention

Alendronate, 4-amino-1-hydroxybutylidene-1,1-diphosphonic acid, and its pharmaceutically acceptable salts are found to be suitable for the treatment of osteoporosis. Alendronate is a specific inhibitor of bone resorption. It has a high affinity for bone mineral matter and is selectively absorbed by bone, where it inhibits osteoclast activity. While it was found that alendronate is suitable for restoring bone loss, there was no indication that it could prevent this bone loss in otherwise healthy people.

The maximum bone mass in women is reached at the age of 30-35 years, after which a decrease in bone mass progresses during life. The rate of this decrease increases in the period of early postmenopause, especially in areas of bone with a high content of trabecular bone.

An average woman has a risk of probably more than 40% of at least one bone fracture associated with osteoporosis during her lifetime. Osteoporotic fractures, especially of the femur, are associated with a marked decline in the quality of life and high cost of treatment. The total costs and incidence associated with all osteoporotic fractures definitely exceed those associated only with a hip fracture, although an accurate assessment has not been carried out.

Currently, the only recommended therapy for the prevention of osteoporosis is estrogen replacement therapy. Along with preventing bone loss associated with decreased endogenous estrogen production, the administration of estrogen can help alleviate postmenopausal symptoms, such as vasomotor instability, vaginal atrophy, and improve the lipid profile with a possible reduction in cardiovascular problems. However, with the doses that are commonly used to prevent bone loss, many women continue to lose it, despite ongoing treatment. In addition, estrogen treatment is also associated with certain serious risks, including endometrial cancer, symptomatic gallbladder disease, and a possible increase in the incidence of breast cancer. Despite the fact that the risk of some of these diseases can be reduced by adding progestins to the treatment regimen or by early endometrial biopsies, most women do not agree with long-term estrogen therapy, mainly due to poor tolerability and doubts about its safety.

It would be desirable to have an agent that could prevent osteoporosis, and not face the risk and possible side effects associated with estrogen.

Description of the invention

This invention relates to a method of preventing osteoporosis in women who have a normal bone mineral density, which comprises administering a prophylactically effective amount of alendronate or a pharmaceutically acceptable salt thereof for a sufficient period of time.

An additional aspect of this invention is a method of reducing the risk of fractures in women, which includes the introduction of a prophylactically effective amount of alendronate or its pharmaceutically acceptable salt for a significant period of time.

Another aspect of this invention is a method of preventing osteoporosis in women in early postmenopause, which includes the introduction of a prophylactically effective amount of alendronate or its pharmaceutically acceptable salt.

In the absence of preventive treatment, the bone microstructure deteriorates as osteoporosis progresses, which leads to a decrease in bone strength per unit mass of bone tissue. It was found that the prophylactic administration of alendronate, in accordance with this invention, maintains the normal microstructure and bone strength. Thus, another aspect of this invention is a method for maintaining a normal microstructure and bone strength by administering a prophylactically effective amount of alendronate or a pharmaceutically acceptable salt thereof.

The definitions used in the description and the claims mean the following.

A prophylactically effective amount is the amount of alendronate or its pharmaceutically acceptable salt, which 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, i.e. sufficient for the treatment of osteoporosis, i.e. restores bone mass loss in a patient currently suffering from osteoporosis.

A significant period of time is an extended period of time, i.e., at least about three years, preferably longer.

Osteoporosis is a condition in which the density of the mineral substance of human bone tissue is more than 2 standard deviations lower than the maximum density of the mineral substance of bone tissue.

Early postmenopause - less than about five years after the cessation of menstruation in women.

Alendronate can be obtained by any of the methods described in US Patent Nos. 5,019,651, 4,992,007 and US Patent Application No. 08/286,151 filed August 4, 1994. Pharmaceutically acceptable alendronate salts include alkali metal salts (eg, Na, K ), alkaline earth metals (eg, Ca), salts of inorganic acids, such as HC1, and salts of organic acids, such as citric acid and amino acids. Sodium salts are preferred, especially the trihydrate form of the monosodium salt.

The compounds of the present invention can be administered in the form of oral dosage forms, such as tablets, capsules (each of which includes dosage forms with delayed or delayed release of the active ingredient), pills, powders, granules, elixirs, paste, tinctures, suspensions, syrups, emulsions and zydis (oral dosage form that dissolves quickly in the mouth). They can also be administered in the form of intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular forms, well known to specialists in the field of pharmaceuticals. As an osteoporosis-preventing agent, the desired compound can be administered in an effective but non-toxic amount.

The scheme of administration of the drug according to the claimed method is selected in accordance with a variety of factors, including the age, weight, sex and clinical condition of the patient; route of administration: the state of the renal and hepatic functions of the patient, as well as in accordance with the specific compound or its salt used. A mid-level clinician can easily determine and prescribe the effective amount of medication that is required to prevent osteoporosis.

Oral doses of the present invention range from 0.05 mg per kg of body weight per day (mg / kg / day) to about 1.0 mg / kg / day. Preferred oral doses for humans may vary in the range of total daily doses of about 2.5-20 mg / day, and the preferred prophylactic amount is 2.5, 5 or 10 mg / day.

Alendronate can be administered as a single daily dose or in divided doses. It is advisable to give a dose outside the meal, preferably from about 30 minutes to 2 hours before eating, for example, before breakfast, to achieve adequate absorption.

In the methods of the present invention, the active ingredient is usually administered in a mixture with suitable pharmaceutical diluents, excipients or carriers (here, carrier materials are referred to under the generic name), which are selected based on the intended route of administration, i.e. in the form of tablets for oral administration, capsules, elixirs, syrups, etc., and in accordance with the usual pharmaceutical practice. For example, for oral administration in tablet form, the active ingredient may be combined with a non-toxic pharmaceutically acceptable inert carrier for oral administration, such as lactose, starch, sucrose, glucose, methylcellulose, croscarmellose sodium, magnesium stearate, mannitol, sorbitol, and so on; for oral administration in liquid form, the components of the drug for oral administration can be combined with any non-toxic pharmaceutically acceptable inert carrier for oral administration, such as ethanol, glycerin, water, etc. In addition, when desired or necessary, to a mixture of active ingredient (s) and inert carrier materials may include suitable binders, lubricants, disintegrators and dyes. Suitable binding agents may include starch, gelatin, natural sugars, such as glucose, anhydrous lactose, non-flowing lactose, beta-lactose and corn sweeteners, natural and synthetic gums, such as gum arabic, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and glypholysilicate. etc. Lubricating agents that are 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 is described in US Pat. No. 5,358,941.

The compounds used in the present process may also be combined with soluble polymer as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide, and the like.

The following non-limiting examples are presented to illustrate the present invention.

Example 1

The women participating in this study were in good health and were between the ages of 45 and 59; were selected randomly among a population of risk living in a specific geographic area. Most of them were in the early postmenopausal period. Less than 15 percent of study participants had any signs of osteoporosis based on x-ray densitometry data with double spin interaction energy.

Each participant was blindly selected in groups receiving placebo, a small dose of alene5 dronate (ALN 2.5 mg per day), a high dose of alendronate (ALN 5 mg per day) or in an openly designated group receiving estrogen / progestin (E / P). The estrogen / progestin-treated group (in the United States) received conjugated estrogen PREMARIN ^r (0.625 mg per day) and medroxyprogesterone acetate PROVERA ^R (5 mg per day), continuously for a calendar month. Outside the United States, the estrogen / progestin-treated group received micronized 17b-estradiol and norethisterone acetate (Trisequens) under a cyclic regimen. All participants whose calcium intake was less than 500 mg per day were advised to increase their calcium intake (both in the form of food and in the form of food additives) above this level. The distribution of groups is shown in Table. 1. The duration of treatment in each group is shown in Table. 2

Table 1

Treatment groups

Formation 1 Formation 2 Group Treatment No No Total BUT placebo 150 300 450 AT ALN 2.5 mg 150 300 450 WITH ALN 5 mg 150 300 D E / R 150 - 150 Total 600 900 1500

ALN = alendronate E / P = estrogen / progestin

table 2

Study design

Year of study Group No 1 and 2 3 and 4 5 and 6 BUT 450 placebo placebo ALB OD or placebo * IN 1 150 ALN 2.5 mg ALN 2.5 mg ALN 2.5 mg AT 2 150 ALN 2.5 mg ALN 2.5 mg placebo IN 3 150 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 C3 150 ALN 5 mg placebo D 150 E / R E / R

ALN = alendronate

OD = optimal dose (2.5 or 5 mg) * Subsequent randomization for the placebo group for the year 5 and 6 U / P = etrogen / progestin

This study was double blind (for women who received alendronate or placebo) for the first two years, at the end of which the first analysis was conducted, this study remained double blind until each participant reached the end of the fourth year of the study, when each participant individually received information. Participants were only informed if they received active treatment with alendronate and, if so, they were treated for two or four years. Participants were not informed about the dose of the test drug. Those participants who remained in ignorance for 5 and 6 years, and the researchers remained in the dark about their treatment during the trial period.

Participants in group A (see Table 2) continued to blindly take a placebo for four years. At the end of the fourth year, these women were informed that they received a placebo for 1-4 years. Then they were offered a choice: further randomization (1: 1) for taking placebo blindly and alendronate at the optimal dose, or termination of participation in the study.

Groups B1 and C2 received 2.5 or 5 mg alendronate, respectively, for six years. Groups B2 and C2 remained at the reception of 2.5 and 5 mg alendronate, respectively, for four years before switching to placebo for the last two years of the study. Those participants who remained in the study for 5 and 6 years remained in ignorance (double-blind study) regarding their treatment with active medication or placebo for 5 and 6 years. The B3 and C3 groups remained on the 2.5 and 5 mg alendronate intake, respectively, only for two years before switching to placebo for the third and fourth year of the study. They stopped taking the test medication after four years.

The participants in group D continued their open estrogen / progestin intake for four years, after which they stopped taking the test drug after four years.

Four years later, women who received alendronate did not show signs of osteoporosis, according to the data, determining the density of mineral matter, bone tissue, while participants who received placebo showed a decrease in the density of bone matter mineral matter. The difference was statistically significant.

Claims (7)

CLAIM 1. A method of preventing osteoporosis in early postmenopause, comprising administering an active agent, characterized in that alendronate or a pharmaceutically acceptable salt thereof is administered as an active agent in a prophylactically effective dose of three years. 2. The method according to p. 1, wherein the alendronate is administered orally. 3. The method according to p. 2, characterized in that the alendronate is administered once a day. 4. The method according to claim 3, characterized in that the salt of alendronate is the trihydrate form of the monosodium salt. 5. The method according to p. 4, characterized in that the dose is from 2.5 to 20 mg per day. 6. The method according to claim 5, characterized in that the dose is selected from the group consisting of 2.5; 5 and 1 0 mg per day. 7. A method of preventing osteoporosis in women in early postmenopause, including the administration of an active agent, characterized in that the trihydrate form of alendronate monosodium salt is administered as an active agent at a dose of 2.5 to 20 mg per day for three years.