CZ259097A3 - Pharmaceutical preparation for reducing risk of bone fractures - Google Patents

Abstract

Alendronate, a bisphosphonate, when administered daily over a substantial period of time, can reduce the rate of vertebral and non-vertebral fractures in post-menopausal women. Further it can reduce the number and severity of fractures. Also, administration of alendronate can prevent spinal deformity, and loss in height.

Description

A pharmaceutical composition for reducing the risk of bone loss

BACKGROUND OF THE INVENTION The present invention relates to a pharmaceutical composition for reducing the risk of fracture, including vertebral and other bone fractures, particularly in postmenopausal women.

AND

BACKGROUND OF THE INVENTION 6 (I || o 9)

Osteoporosis is a metabolic disease that is cha,. »T-o is characterized by a decrease in bone mass and strength as a function of age. The disease is characteristic of women after menopause, although it may also occur in older men. The most common clinical manifestations of osteoporosis are vertebral fractures and fractures of the hip and wrist joints.

Fractures associated with osteoporosis are very common and occur in approximately 27% of women over 65 years of age and in approximately 60% of women over 80 years of age. Vertebral fractures are often not diagnosed, although they are usually accompanied by pain and limit the patient's ability to perform normal daily tasks. Multiple vertebral fractures can cause kyphotic posture, chronic back pain and helplessness.

Up to 20% of women experience hip fractures, which can have serious consequences. Mortality of up to 20% within six months after hospitalization has been reported.

A number of treatments are currently used to prevent and treat osteoporosis, including hormone replacement therapy (estrogens), administration of calcitonin, etindronate (a bisphosphonate class), ipriflavone, fluorides, vitamin D, and calcium. There are very different procedures used in different regions of the world.

Although it has been reported that some of the above-mentioned substances increase the amount of inorganic substances in bone tissue (BMD), it is not possible to establish a correlation between an increase in MBD and a reduction in the incidence of bone fractures. Although the number of fractures increases when BMD decreases, the number of fractures does not necessarily decrease when BMD increases. For example, when fluoride is administered, BMD increases but at the same time fractures in the hip area increase.

SUMMARY OF THE INVENTION

It has now been found that the administration of alendronate (4-amino-l-hydroxybutylidene-l, 1-bisphosphonate) reduces ⁰ The risk of fractures in postmenopausal women.

The present invention provides a pharmaceutical composition for reducing the risk of bone fracture comprising, as an active ingredient, alendronate or a pharmaceutically acceptable salt thereof.

By administering the composition, the risk of bone fracture can be reduced. This risk can be reduced, in particular, by prolonged administration of the composition, whereby the risk further decreases. The risk is not only reduced for hip and wrist fractures, but also for ⁰ vertebral fractures. Therefore, it is also possible to prevent deformations of the spine associated with loss of body height. Even if a vertebral fracture occurs, the fracture is less severe.

It has been shown that fracture incidence can be reduced especially with long-term administration of alendronate. The risk of vertebral fractures can be reduced by at least 40%, probably by up to 45% and basically by up to 48%. This decrease is statistically significant compared to placebo. Taking into account the total number of vertebral fractures (as opposed to the number of θ persons with these fractures), this is a reduction of at least 50%, in some cases up to 60% and in principle up to 63% per 100 patients compared to placebo. In addition, the deformation of the spine can be stopped. For other fractures it is possible to achieve a reduction in incidence and leaspo of 20%, in some cases up to 25% and in principle up to 29%. In addition, the risk of developing all fractures after three years of administration is lower than after two years of administration of the pharmaceutical composition.

In this case, the BMD also increases, which means that after a prolonged period of time, the composition not only reduces bone sorption, but even aids in the formation of thicker bone tissue. lying at least two or two and a half times the standard deviation below the normal value for a woman after menopause.

Overview of the drawings

Fig. 1 shows a graph showing the time in months on the abscissa axis, the ordinate on the time to the first fracture (procedure of Example 2). This is the result of five clinical trials. The results are statistically significant at the end of the third year.

Fig. 2 is a graph depicting a reduction in stature in alendronate or placebo groups given a standard error.

Fig. 3 is a graph for reducing the height of a subject in patients who have a vertebral fracture during follow-up. A standard error is also listed.

The following terms will be used throughout the application and will now be explained in more detail.

An effective amount means at least an amount that reduces the risk of fracture but is less than a toxic amount.

A longer period of time means a period sufficient to increase the 5 BMD value in the patient's bone tissue so that the tissue is more resistant to fracture. A typical period is more than two years, preferably more than three years.

Essentially daily means that daily administration is contemplated, but the patient may be omitted and the dose may be inadvertently missed. The overall effect of maximax corresponds to daily drug administration.

More advanced age means the age of 65 heaven more years.

Lower than advanced age means age under 65 years.

PYR means the number of risk years in the group, the value of 15 is the number of persons in the group multiplied by the number of years of the experiment.

Alendronate can be prepared by the processes disclosed in US 5,019,651, US 4,992,007, and US Pat. No. 20/286,151, filed Aug. 4, 1994. Pharmaceutically acceptable salts thereof include alkali metal salts, such as sodium and sodium salts. potassium salts, alkaline earth metal salts such as calcium salts and salts with inorganic acids such as hydrochlorides, as well as salts with organic acids such as citric acid or amino acids. Preferred is the sodium salt, especially in the form of the trihydrate.

They may be administered orally, for example in the form of tablets, capsules (both being controlled release formulations), pills, powders, granules, elixirs, pastes, elixirs, suspensions, syrups, solubilized forms, emulsion. The compositions may also be intended for intravenous administration by injection or infusion, intraperitoneally, subcutaneously or intramuscularly. An effective but non-toxic amount is administered.

In patients, the composition is administered substantially daily for an extended period of time. That is, the composition should be administered at least half a day in the treatment period for at least one year, preferably longer, for three or more years. Preferably, the composition is administered daily for at least three years to achieve optimal results. This may result in shorter periods in which the drug is not administered. Because alendronate persists in bone tissue for a very long time, it is sufficient that the drug is administered at least half the days in the last six months. It can also be administered cyclically, that is to say for a period of time, for example a month, then the administration is discontinued (and optionally another substance having a similar effect or hormones is administered), after which the alendronate is restarted.

Doses are selected depending on a number of factors such as age, weight of the patient, sex and general condition, severity of the disease, the route of administration of the patient's liver and kidneys, and the drug selected.

When administered orally to prevent fractures, 0.05 mg / kg per day to 1.0 mg / kg of active ingredient per day will be administered. Preferred daily dosages for oral administration may range from 2.5 to 50 mg, for example 2.5, 5, or 20 mg per day. Doses may vary at different times of administration, for example, a dose of 20 mg per day may be given for two years followed by a 5 mg dose per day. Alternatively, a lower dose, for example 5 mg, may be administered for a long time. daily.

The alendronate composition may be administered once daily or in divided doses. It should not be administered with food, preferably administered 30 minutes to 2 hours before a meal, for example before breakfast, to achieve good absorption.

The active agent is typically administered together with pharmaceutical diluents, carriers or excipients according to the type of pharmaceutical composition, such as tablets for oral administration, capsules, elixirs, syrups and the like in accordance with conventional practice. For example, for oral administration in the form of tablets or capsules, the active ingredient may be admixed with nontoxic inert carriers suitable for such administration, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, sorbitol, and the like. use inert liquid carriers such as ethanol, glycerol, water and the like.

In addition, binders, glidants, disintegrating agents and coloring agents may also be included in the composition as desired. Suitable binding agents are, for example, starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-lactose, beta-lactose, sweeteners based on corn, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, sodium crosslinked carmellose salt and the like. Glidants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. A particularly suitable tablet composition has been described in US 5,358,941.

The active compounds can also be coupled to soluble polymers as carriers. These may be polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide and the like.

Clinical trials were conducted on selected patients who had a decrease in spine BMD compared to the general population, but there were no predominant vertebral fractures, so that the group was as consistent as possible with the general population. At the same time the clinical manifestations of the disease were evaluated according to the following aspects:

Body height

Reducing body height is one of the consequences of vertebral fractures. In several years, due to osteoporosis fractures, a patient may lose 10 to 20 cm from the height of his body. This is the result of a reduction in vertebrae and kyphosis, resulting in reduced mobility and compression of the abdominal and thoracic cavities. Body height measurement is simple, inexpensive, reproducible and is done without the use of radiation. This value makes it easy to detect differences between groups. Although in some patients the height of the figure may reflect postural changes or changes in the 15 platelets, comparing the treatment and placebo groups in the blind test accurately determines the effect of the composition on vertebral fractures. with the placebo group (p =

0.005). Nonparametric and curve analysis for individuals were also statistically significant (p = 0.003 and p is less than 0.001). All analytical methods used confirm that the rate of body height reduction decreases after administration of alendronate, more demonstrable after three years of administration (compared to two years of administration).

In addition, the overall decrease in stature height after accidental vertebral fracture in placebo-treated patients was higher than in patients treated with alendronate. Patients treated with placebo experienced an average decrease in height of

This difference shows that the active ingredient not only reduces the risk of fracture but also reduces its severity.

Vertebral fractures

Calculations of prevalent and random vertebral fractures were performed by comparing baseline vertebral height in individual patients with the corresponding population height (predominant fractures) and height during follow-up (random fractures). Only actual vertebral heights were used to determine the predominant fractures. The vertebral height, which is at least three times the standard deviation below the reference value in the population, was defined as the predominant fracture. A 20% reduction relative to baseline height with an absolute reduction of at least 4 mm was assessed as a random fracture.

After three years of follow-up, the reduction in vertebral fractures was statistically significant (p = 0.034) and also clinically favorable (48%, 95% C.I. = (72%, 5%)). The reduction in fracture was homogeneous in the various subgroups selected by dose, age (below or above 65 years) and the presence or absence of predominant vertebral fractures.

Deformation of the spine

The spine deformation index, SDI, was calculated for each patient according to Minne et al., 1988, Bone and Min. 3: 335-349. This is done by dividing the vertebral height of each individual by the corresponding height of his thoracic vertebrae (T4), namely the front, posterior, and central heights to obtain 39 vertebral height ratios. T4 was chosen as the reference height because it rarely breaks and can therefore be used to adjust the height difference of the figure as well as to adjust the difference between baseline height and height during observation where artifical changes in the determination may occur apparent vertebral height after a period of observation. Each height ratio is then compared to the ratios in the general population and those ratios that are below the lowest value for the population standard add up (absolute distances below the norm) to obtain the SDI.

Using this index, 41% of patients who received placebo had progressive deformities compared to 33% of the alendronate group. This is a statistically significant difference (p = 0.028). In addition, there was a statistically significant difference (p = 0.54) in the distribution of SDI changes in both groups.

Alendronate, administered over an extended period of time also reduces the risk of other fractures. For example, in patients receiving alendronate, the cumulative fracture rate after three years was 9.0%, and the overall fracture rate (without vertebral fractures) was 3.26 per 100 PYR. In contrast, in patients receiving placebo, the cumulative fracture rate after three years was 12.6 and the overall incidence (without vertebral fracture) was 4.45 per 100 PYR. The relative overall risk reduction of these fractures (without vertebral fractures) was 29% at 95% confidence limits (0.3%, 49.8%) and at p = 0.043. Similar results were obtained using other statistical methods.

It is also surprising that the reduction of the risk of developing all types of fractures is the same in people of advanced age (at least 65 years) and in people under 65 years of age. Thus, it is clear that even in the elderly with osteoporosis, the risk of fracture can be reduced by administering alendronate.

In addition, it has been shown that a greater reduction of this risk can be achieved in particular by prolonged administration of the compounds, the probability of success increases with the duration of administration.

The following examples are intended to illustrate the invention but do not limit its scope.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Women after menopause with a low mineral content in vertebrae, defined as a low BMD of 0.92 g / cm ² or less (+ or - 0.02 g / cm ² ) as measured by DPX (Lunar) or 0.80 g / cm ² or lower (+ or -0.02 g / cm ² ) according to the QDR (Hologic) method were considered to be suffering from osteoporosis. This definition corresponds to BMD values that are approximately ⁵ 2.5 times the standard deviation below the mean

BMD for adult Caucasian female breed (white) in the US before menopause. Patients were otherwise healthy on the basis of medical history, physical examination and laboratory values.

Data were collected from 1602 persons assigned to ⁰ five groups. 1012 patients were treated with alendronate, which was administered: A) 5 mg daily for two or three years, B) 10 mg daily for two or three years, C) 20 mg daily for two years, D) 2.5 mg daily for two years, E) 40 mg daily for three months and then 2.5 mg daily for 21 months; or F) 20 mg daily for 2 years. 590 patients received placebo. In addition, all patients were instructed on diet and calcium supplementation. Almost all 500 mg of elemental calcium (in the form of calcium carbonate) was given extra calcium.

The following Table 1 shows the number of patients, θ the number of fractures (without vertebral fractures) and PYR for each group. The total number of fractures (without vertebral fractures) was 133, of which 60 in the placebo group and 73 in the alendronate group. The total number of PYRs was 3587, of which 1347 were in the placebo and

2240 in the alendronate group.

group

N

31

192

205 15

71

91

Sum of 590

Table 1 L A C E B 0 number break. PYR 3 49 21 486 17 529 3 128 16 154 60 1,347 1

A L E N D

N number of breaks. PYR 93 8 161 286 28 720 311 17 805 140 2 256 182 18 298 012 73 2 240

ALEND means a group treated with alendronate

The following Table 2 shows the number of fractures per 100 PYR for each of the five groups except vertebral fractures. The placebo group received between 2.34 and 10.38 fractures per 100 PYR. For the alendronate group it is 0.78 to 6.04. The last column of Table 2 gives the ratio for the treatment and placebo groups. These values range from 0.33 to 0.90 and confirm that the values for the alendronate groups are always lower than for the placebo group.

Table 2

Fractures per 100 PYR (without vertebral fractures)

Placebo Group Alendronate ALN / PLC ratio 1 6.07 4, 97 0.82 2 4.32 3, 89 0, 90 3 3, 21 2.11 0, 66 4 2, 34 0.78 0.33 5 10.38 6.04 0.58 Summary 4.45 3.26 0.73 The figures were analyzed to be can be determined a compelling difference between sick advanced age (65 and

and sick, younger than 65 years. Cox's model of relative risk, including age, was also used. In classifying age as a continuous variable, age was not a significant factor in any age category. The relative risk was always theoretically equal to 1. This means that there is no difference in effect in patients in both age categories. The results of these experiments are summarized in Tables 3 and 4 below. An analysis of the effect of duration of administration on the effect is shown in Table 5 below.

Tab u 1 k a 3 5 Fractures in advanced persons age (except vertebrae) Placebo Alendronate reduction risika N 284 479 Number of cases 34 37 10 PYR 636 1036 Cumulative occurrence 14.6% 9.4% 36% Number of fractures per 100 PYR 5.35 3.57 33% 15 Dec Tab u 1 k a 4 Fractures in persons below 65 years ( (except vertebrae) Placebo Alendronate reduction risika 20 May N 306 533 Number of cases 26 36 PYR 711 1204 Cumulative occurrence 10.8% O O O, O f xj -o 21% Number of fractures 25 per 100 PYR 3, 66 2, 99 18%

Table 5

5 Incidence of fractures in individual years (except reverses' Year Placebo Alendronate ALN / PLB ratio 1 4.88 3.53 0.72 2 4.09 3, 60 0, 88 10 3 4.27 2.12 0.50 T and b u 1 k and o 15 Dec Expected and real fracture rate ( except vertebrae for a group, to which alendronate was administered Year Actual occurrence Expected occurrence Actual 20 May 1 33 4 6,8 0, 71 2 30 41, 5 0.72 3 10 15.2 0, 66

The third column shows the values that could be expected without treatment with alendronate.

Example 2

Based on the pooling of all groups, kulative fracture-free ratios were calculated and appropriate intervals were determined using survival tables to more easily represent results. Log values were used to compare groups with different treatments. The relative risk was calculated according to the Cox model. Figure 1 shows the cumulative latent proportion of fracture-free persons over time. Obviously, the differences increase in the third year of alendronate administration.

Tables 7 and 8 below summarize statistical data for the alendronate and placebo groups. At the end of the third year of follow-up, the cumulative proportion of patients with clinical fractures was 0.090 in the alendronate group and 0.126 in the placebo group. The reduction of fracture risk with the exception of vertebral fractures was 29.3% for the treatment group at 95% confidence limits (0.3%, 49.8%), p = 0.047.

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Example 3

Osteoporosis in women was evaluated in the same manner as in Example 1. At the start of the experiment, only 20% of women had vertebral fractures.

Data were collected from 881 patients, assigned to two groups following the same procedure. One group was followed in the United States, the other in Canada, Mexico, Europe, Israel, South America, Australia and New Zealand. The data of both groups were then combined. 526 patients were treated with alendronate by any of the following: A) 10 mg daily for three years, B) 5 mg daily for three years, C) 20 mg daily for 2 years, and then 5 mg daily for one year. 355 patients received placebo. In addition, dietary supplements were given and calcium supplementation instructions were given. Almost all patients received calcium, 500 mg of elemental calcium in the form of calcium carbonate daily.

Verification of vertebral fractures and SDI spine deformities was based on measurements of spine X-ray images at the start of treatment and then after one, two and ares years. Three vertebrae were applied to each vertebra at the top with three at the lower edge of each of the 14 vertebrae from T4 to L5. The coordinates of these marks were entered as X and Y coordinates with the mouse into the computer program and entered as the distance between the marks in mm. By repeating the procedure it was possible to detect differences between the heights of the individual vertebrae at the above time intervals.

Example 4

Vertebral fractures

The 39 women of Example 1 developed at least one vertebral fracture over a period of three years, as determined by a change in their vertebral height. They were 22 out of 355 women (6.20%) in the placebo group and 17 out of 526 women (3.23%) in the alendronate group. The díl10 part is statistically significant (p = 0.034) in favor of the alendronate treated group.

The relative risk of fracture in subjects treated with alendronate compared to the placebo group is 0.52 (95% m CI = (0.28, 0, 95)). years of healing.

In addition, in patients with more than one accidental vertebral fracture, the proportion of patients with two or more fractures was much higher in the patients receiving placebo (15/22, 68%) compared to the alendronate group (3 (17, 18%). Due to the lower number of affected patients and the lower number of fractures per patient, the number of fractures per 100 patients was significantly lower in the alendronate (4.2) group than in the placebo group (11.3).

In addition, fractures in the treatment group were less severe than in the placebo group. The following Table 9 shows the number of slight fractures (end plate deformities) and serious cases (vertebral compression) in each of the above groups.

Table ^{Τ ΥΡΥ} observed fractures

Placebo

Alendronate

Mild fractures 3/22 (13.6%) 6/17 (35.3%

Severe fractures 19/22 (86.4%) 11/17 (64.7% ’

Example 5

Spine deformation index

The spine deformation index, SDI, is similar to fracture rates. 41% of the women in the placebo group experienced an increase in deformation compared to 33% of the women in the alendronate group (p = 0.028 for the chi ² -test). This difference is even greater after three years than after two years (38% placebo, 33% alendronate).

Overall, the average change from baseline

0.082 (placebo) and 0.041 (alendronate). In addition, in women with an increase in deformation, this value averaged 0.212 (placebo) and 0.143 (alendronate). In the Wilcox pooled test, the cut-off values for statistical significance (p = 0.054) were reached for distribution of SDI change compared to baseline between the placebo and alendronate treated groups.

Example β

Body height

Body height was measured in all patients using Harpenden stadiomentru, which can be measured to the nearest mm, it is the most accurate current measurement method. The height was measured three times: if any two results differed by more than 4 mm, the fourth and fifth measurements were taken. The average of the measurements was used as the measured value.

The mean figure height change over the three years of treatment was -4.61 mm (placebo) and -3.01 mm (alendronate), a statistically significant difference (p = 0.005, 95% CI = (0.49, 2.71) mm)). The difference after three years was greater than the difference after two years (-3.2 mm for placebo and -1.9 mm for alendronate).

In addition, a response time graph was constructed for each individual. These graphs are shown in Figures 2 and 3.

Claims (6)

A pharmaceutical composition for reducing bone risk i., θ 2 ° ^0Ί fractures, characterized in that jjako an active ingredient, alendronate or its farmage | ^ go ^ jk acceptable salt thereof. | f'o 2. A pharmaceutical composition according to claim 1 which is intended to reduce the risk of vertebral fractures. 3. A pharmaceutical composition according to claim 1 which is intended to reduce the risk of fracture except for vertebral fractures. Pharmaceutical composition according to claims 1 to 3, characterized in that it is intended for oral administration. Pharmaceutical composition according to claims 1 to 3, characterized in that it is administered in a daily dose of 2.5 to 20 mg of active ingredient. Pharmaceutical composition according to claims 1 to 5, characterized in that it is administered daily for at least two years.