SK159597A3 - Use of alendronate for the prevention of osteoporosis - Google Patents

Abstract

Alendronate, an aminobisphosphonate, can prevent osteoporosis in early post menopausal women.

Description

Technical field

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

BACKGROUND OF THE INVENTION

Alendronate, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and its pharmaceutically acceptable salts have been found useful in the treatment of osteoporosis. Alendronate is a specific inhibitor of bone resorption. It has a high affinity for bone minerals and selectively passes to the bones where it inhibits osteoclast activity. Although alendronate has been shown to be useful in restoring bone loss, there is no indication that it can prevent bone loss in otherwise healthy individuals.

The peak of bone mass in women is reached at approximately 30 to 35 years and then bone mass decreases over time. The rate of decline is accelerated during the post-menopausal period, particularly in areas with a high fraction of the beam.

The average woman is likely to have more than 40% chance of developing at least one osteoporotic fracture during her life. Osteoporotic fractures, especially in the case of the hip joint, are associated with a significant reduction in quality of life and a high cost of treatment. Although no accurate estimates are available, the total cost of treatment and mortality associated with osteoporotic fractures surely significantly outweighs the cost and mortality of the hip fracture alone.

At present, the only proven prevention of osteoporosis is estrogen replacement therapy. Together with the prevention of bone loss associated with decreased estragon production, administration of estragon can help reduce postmenopausal symptoms such as vasomotor instability, vaginal atrophy and can help improve lipid profile with a likely reduction in the possibility of cardiovascular complaints. At doses that are commonly used to prevent bone loss,

However, many women continue to lose bone mass despite treatment. In addition, tarragon treatment is also associated with some serious risks, including endometrial cancer, symptomatic gallbladder disease, and a possible increase in breast cancer. Although some of these risks may be reduced by the addition of a progestin in the course of treatment or by an annual endometrial biopsy, a large proportion of women do not accept long-term tarragon therapy mainly due to poor tolerance and safety reasons.

It would be advantageous to have a composition which can prevent osteoporosis while avoiding the risks and possible side effects associated with tarragons.

SUMMARY OF THE INVENTION

The invention relates to a method of preventing osteoporosis in women with normal bone mineral density comprising administering a prophylactically effective amount of alendronate or a pharmaceutically acceptable salt thereof for a sufficiently long period.

Another aspect of the invention is a method of reducing the risk of fractures in women by administering a prophylactically effective amount of alendronate or a pharmaceutically acceptable salt thereof for a sufficiently long period of time. Yet another aspect of the invention is a method of preventing osteoporosis in women shortly after menopause by administering a prophylactically effective amount of alendronate or a pharmaceutically acceptable salt thereof.

If preventive treatment is not performed, the bone microstructure is destroyed along with the ongoing course of bone loss, leading to a decrease in bone strength per unit of bone mass. The preventive administration of alendronate of the present invention has been found to protect normal microstructure and maintain normal bone strength. Another aspect of the present 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.

The following definitions shall apply throughout the specification and claims:

-3, "Prophylactic effective amount": an amount of alendronate or a pharmaceutically acceptable salt thereof, sufficient to prevent osteoporosis in women not yet suffering from osteoporosis. This amount may or may not be a pharmaceutically acceptable amount, i. an amount sufficient to treat osteoporosis, i. restoring bone mass in a patient suffering from osteoporosis.

"Substantial time": an extended period, i. at least about 3 years, and preferably longer.

'Osteoporosis': a condition in which the bone mineral density of the patient is more than two standard deviations below the peak bone mineral density.

'Shortly after menopause': less than approximately 5 years after the end of the menstrual periods of women.

Alendronate may be prepared according to any of the procedures described in US Patent Nos. 5,019,651, 4,992,007 and US Patent Application Ser. No. 08 / 286,151 of Aug. 4, 1994, all of which are incorporated herein by reference. Pharmaceutically acceptable salts of alendronate include alkali metal salts (e.g. Na, K), alkaline earth metals (e.g. Ca), salts with inorganic acids such as HCl, and salts with organic acids such as citric acid and amino acids. Preferred are the sodium salt forms, especially the trihydrate form of the monosodium salt.

The compounds of the present invention can be administered in oral dosage forms such as tablets, capsules (both also include sustained release or time release formulations), pills, powders, granules, elixirs, pastes, elixirs, suspensions, syrups and emulsions . Similarly, they can be administered in intravenous (single or infusion), intraperitoneal, subcutaneous form, i.e., forms well known to those skilled in the art of pharmacy. An effective but nontoxic amount of the desired compound can be used as an agent for preventing osteoporosis.

The dosage regimen utilizing the method of the invention is selected according to a variety of factors including the age, weight, sex and clinical condition of the patient; liver function and kidney function; and in particular the compound or salt used. A physician of ordinary skill in the art can readily determine an effective amount of a medicament for preventing osteoporosis.

The oral doses of the present invention will range from 0.05 mg / kg body weight per day (mg / kg / day) to 1.0 mg / kg / day. Preferred oral doses in humans may range from a total daily dosage of about 2.5 to 20 mg / day during the effective treatment period, and a preferred prophylactic amount will be 2.5, 5, or 10 mg / day.

Alendronate may be administered in a single daily dose or in divided doses. It is desirable not to administer a meal, preferably at least 30 minutes to 2 hours before a meal, such as breakfast, to allow proper absorption.

In the methods of the present invention, the active ingredient is typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier materials"), suitably selected with respect to the intended form of administration, i. oral tablets, capsules, elixirs, syrups and the like, and in accordance with conventional pharmaceutical practice. For example, for oral administration in the form of a tablet or capsule, the active ingredient may be combined with an oral non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, croscarmellose sodium, magnesium stearate, mannitol, sorbitol and the like; for oral administration in liquid form, the drug components may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, if necessary, suitable binders, glidants, disintegrants and colorants may be added to the mixture of the active ingredient (s) and inert carriers. Suitable binders may include starch, gelatin, natural sugars such as glucose anhydrous lactose, free-flow lactose, beta-lactose and cereal sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and waxes. Similarly. Glidants 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 that described in US Patent 5,358,941.

The compounds used in the practice of the invention may also be coupled with soluble polymers as targeted drug carriers. Such polymers may

Include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylate and the like.

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

DETAILED DESCRIPTION OF THE INVENTION

Example 1

The women who participated in this study had good general health, aged between 45 and 59 years, and were randomly selected from a target population living in a defined geographical area. Most are shortly after menopause. Less than 15% of the participants had osteoporosis on the basis of dual-energy X-ray densitometric measurements. Each patient is randomized to receive placebo, low dose alendronate (ALN 2.5 mg / day), high dose alendronate (ALN 5 mg / day) or open labeled estrogen / progestin (EP). The estrogen / progestin group (in the US) received conjugated estrogen PREMARIN® (0.625 mg / day) and medroxyprogesterone acetate PROVERA® (5 mg / day) taken continuously during the calendar month. In addition to the USA, the estrogen / progestin moiety receives micronized 17b-estradiol and norethisterine acetate (Trisequens) in cyclic mode. All patients with calcium intake less than 500 mg / day are required to increase calcium intake (either on a diet or with other medicines) above this level. The group distribution is shown in Table 1. The treatment duration for each group is shown in Table 2.

Table 1

Treatment groups

Layer 1 Layer 2 Group treatment A N Pretty A placebo 150 300 450 B ALN 2.5 mg 150 300 450 C ALN 5 mg 150 300 450 D E / P 150 150 Pretty 600 900 1500

-6ALN = alendronate E / P = estrogen / progestin

Table 2

Study scheme

Years of study Group N 1a2 3a4 5a6 A 450 placebo placebo ALN OD; alebc 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 B3 150 ALN 2.5 mg placebo 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 / P E / P

ALN = alendronate

OD = optimal dose (either 2.5 or 5 mg) * = Subsequent randomization to placebo at years 5 and 6 prolongation

E / P = estrogen / progestin

The studies are performed twice in the blind (for women receiving alendronate or placebo) for the first two years at the end of which a first analysis is performed. The study remains double-blind until each patient reaches the end of the fourth year of study, when each patient is notified of the treatment individually. Patients are only informed if they are actively treated with alendronate and, if so, whether they have been treated for two or four years. Patients are not informed about the dose of drug used. Patients remain blinded in years 5 and 6 and the study

-Ί workers are not familiar with the method of treatment even during an extended period.

Patients in group “A” (see Table 2) are given placebo for the next four years. At the end of four years, these women are informed that over the years 1-4 they received a placebo. They are given the opportunity to participate in another random (1: 1) study between placebo blind and alendronate and “optimum blind dose or discontinue the study.

Groups B1 and C1 receive 2.5 or 5 mg alendronate for 6 years. Groups B2 and C2 remain at 2.5 and 5 mg alendronate, respectively, for 4 years prior to the change to placebo for the last two years of the study. Patients who continue the study at years 5 and 6 continue blind (twice blind) for active drug or placebo at years 5 and 6. Groups B3 and C3 remain on 2.5 and 5 mg alendronate only two years before the change. placebo for the third and fourth year of the study. They are no longer in the study after the fourth year. Patients in Group B continue treatment with open labeled estrogen / progestin for four years and then discontinue the study.

After four years, women receiving alendronate do not develop signs of osteoporosis, as measured, for example, by decreasing bone mineral density, while women receiving placebo show a loss of bone mineral density. The differences are statistically significant.

Claims (3)

PATENT CLAIMS Use of alendronate or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention of osteoporosis in post-menopausal women. Use according to claim 1, wherein the alendronate is administered by mouth. The use according to claim 1, wherein the alendronate salt is the monosodium salt trihydrate.