MXPA97006275A - The use of alendronate to prepare compositions to reduce the risk of vertebra fractures - Google Patents

Abstract

Alendronate, a bisphosphonate, when administered daily for a substantial period, may reduce the rate of vertebral fractures in post-menopausal women, and may reduce the number and severity of fractures, and the administration of alendronate may prevent Deformity of the spine, and loss of pe

Description

THE USE OF THE RLENDRONFLY PRRR PREPRRRR COMPOSITIONS PRRR REDUCE THE RISK OF VERTEBRAL FRRCTURRS BRIEF DESCRIPTION OF THE INVENTION This invention relates to a method for reducing the risk of vertebral fractures in post-menopausal women by administering an effective amount of alendronate, a bis-osphonate.

BACKGROUND OF THE INVENTION Osteoporosis is a metabolic disease characterized by a reduction in age-related bone mass and resistance. The condition mainly affects the past-menopausal women, although it can also affect elderly men. The most common clinical manifestations of osteoporosis are fractures of the vertebrae, hip and wrist. Fractures related to osteoporosis are very common, occurring in approximately 27% of women over 65 years of age and er > approximately 60% of men over 80 years of age. Vertebral fractures are often not diagnosed, although they are often accompanied by pain, and may limit the patient's ability to perform daily activities. Multiple vertebral fractures can lead to kyphotic posture, chronic back pain and disability. A number of therapies are commonly used to prevent and treat osteoporosis, including the replacement of hormones (estrogen), calcitonin, etidronate (a bisphosphonate), ipriflavone, fluoride, vitamin D, and calcium. The degree of treatment varies worldwide. Although it has been reported that some of the aforementioned treatment agents can increase the density of bone minerals (BrID), there is no established correlation between increased BMD and a reduction in vertebral fractures. While low BMD correlates with an increased fracture rate, a higher BMD does not necessarily correlate with a reduction in fractures. For example, it has been shown that fluoride increases BMD, but the rate of hip fractures also increases.

DESCRIPTION OF LR INVENTION It has been found in accordance with this invention that the administration of alendronate (4-arnino-1-hydroxy-butylidene-1, 1-bisphosphonate) is useful in reducing the risk of vertebral fractures in post-menopausal women osteoporotic. Therefore, this invention provides a method for reducing the risk of vertebral fractures by administering an effective amount of alendronate or a pharmaceutically acceptable salt thereof to osteoporotic women. In addition, this risk reduction is maintained and even reduced with the long-term administration of alendronate. Another objective of this invention is to reduce the risk of spinal deformity by administering an effective amount of alendrona + or a pharmaceutically acceptable salt thereof for a substantial period. Another aspect of this invention is to prevent the loss of height by administering an effective amount of alendronate or a pharmaceutically acceptable salt of the ism over a substantial period. Yet another aspect of this invention is a method for reducing the severity of vertebral fractures in patients suffering from said fracture by administering alendronate for a substantial period before suffering fracture. It has surprisingly been found that the incidence of vertebral fractures can be reduced when an effective amount of alendronate is administered over a substantial period. It is estimated that the reduction in the risk of vertebral fractures is at least about 40%, preferably at least about 45%, and even more preferably about 48%; it was found that this reduction is statistically significant (when compared with a placebo). When the total number of vertebral fractures was calculated (as opposed to the number of patients with fractures), alendronate produces at least a 50% reduction, preferably at least about 60% and even more preferably at least about 63% in the rate of vertebral fractures per 100 patients, when compared with placebo. Likewise, alendronate produces a statistically significant reduction in the progression of vertebral deformity, compared with patients treated with placebo. In addition, the risk rate for vertebral fractures (compared to placebo) is lower after 3 years of administration than after one or two years of administration. It has been found in accordance with this invention that the increase in bone mineral density observed with the administration of alendronate is positively associated with a reduction in vertebral fractures, a reduction in the deformity of the spine and a retention of height. This indicates that when administered for a substantial period, alendronate not only decreases bone resorption, emo also acts positively to produce a reinforced bone. Women receiving alendronate according to this invention suffer from osteoporosis, that is, they have a bone mineral density (BMD) that is at least about two or two and a half standard deviations lower than the normal value of pre-existing women. - enopáusicas.

DESCRIPTION OF LR FIGURE Figure 1 is a graph showing the response profile over time of the reduction of the height of all patients in the groups treated with placebo and treated with alendronate. The average change and ± EE were observed. Figure 2 is a graph showing the response profile over time of the reduction in height in patients who have an incidental vertebral fracture during the study. The average change and ± EE is shown. Throughout the specification and the claims, the following definitions will apply: "Effective amount" will mean at least the amount of alendronate that is required to provide a reduction in fracture risk, but less than a toxic amount. "Substantial period" means an amount of time that is large enough to allow the bones of the patient to have an increased density of bone minerals (BMD) and an increased resistance thereof, so that they are more resistant to fractures. A typical substantial period is a long period, and exceeds two years, and preferably exceeds three years. "Substantially on a daily basis" means that the administration is intended to be daily, but the patient may occasionally inadvertently skip doses, so that the overall effect is not different from that observed when a patient receives the dose daily. "Elderly" means that age is equal to, or greater than, 65 years of age. "Not elderly" means that the age is less than 65 years old. Alendronate can be prepared in accordance with any of the methods described in the patents of F.U.A. 5,019,651, 4,992,007, and the application series of E.U.fl. No. 08 / 286,151 filed August 4, 1994, each of which is incorporated herein by reference. Pharmaceutically acceptable salts of alendronate include alkali metal salts (e.g., Na, K), alkaline earth metal salts (e.g., Ca), salts of inorganic acids, such as HCl, and salts of organic acids such as citric acid and amino acids. . Sodium salt forms are preferred, particularly the t-hydrated form of monosodium salt. The compounds of the present invention can be administered in oral dosage forms, such as tablets, capsules (each of which includes controlled release or sustained release formulations), pills, powders, granules, elixirs, pastes, tinctures, suspensions, syrups and emulsions. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, all using forms well known to those skilled in the pharmaceutical arts. An effective but non-toxic amount of the desired compound can be used as an agent to prevent fractures. Patients will preferably receive alendronate substantially daily for a substantial period for the effect to be observable. This means that the patient will receive alendronate at least half of the days in a treatment period, with the treatment period lasting at least one year, and is preferably longer, up to and exceeding two, three or more years. In a preferred embodiment, the patient will receive alendronate substantially daily for at least three years to experience the greatest benefit. It is anticipated that a patient receiving such long-term therapy may experience occasional periods when alendronate is not administered, but since alendronate has a long-lived active life in the bone, this is considered to be within the scope of the invention provided that the patient receives alendronate at least half of the days in the previous six-month period. Likewise, it is within the scope of this invention that alendronate is administered on a cyclic regimen, ie, the patient can receive alendronate for a given period (e.g., one day, weekly, monthly, seri- nually, or for several months) and then may not receive alendronate (and other inhibitors or promoters of bone absorption, and / or hormone therapy may or may not be administered) for a second period (either the same time or different from the first period), and receive the alendronate therapy again. The dose regimen using the claimed method is selected in accordance with various factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the liver and kidney function of the patient; and the particular compound or salt thereof used. The doctor or expert clinician can easily determine and prescribe the effective amount of the drug that is required to prevent bone fractures. The oral doses of the present invention, when used to prevent bone fractures, will vary from 0.05 mg per kg of body weight per day (g / kg / day) to about 1.0 mg / kg / day. Preferred oral doses in humans may vary from total daily doses of about 2.5-50 mg / day during the effective period of treatment, and a preferred amount is 5, 10 or 20 mg / day. Doses may vary over a period of time, in which a patient may receive a high dose, such as 20 mg / day during a treatment period, such as two years, followed by a lower dose, such as 5 mg / day more ahead. Alternatively, a low dose (ie, about 5 mg) may also be administered over a longer period with similar beneficial effects.

Alendronate can be administered in an individual daily dose or in a divided dose. It is convenient that the dose be administered in the absence of food, preferably around 30 minutes to 2 hours before food, so that breakfast allows adequate absorption. In the methods of the present invention, the active ingredient is typically administered in admixture with suitable diluents, excipients or pharmaceutical carriers (collectively referred to herein as "carrier materials"), conveniently selected with respect to the desired form of administration , ie tablets, capsules, elixirs, syrups and the like oral and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of a tablet or capsule, the active ingredient can be combined with an oral, non-toxic and pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like; for oral administration in liquid form, the oral components of the drug can be combined with any oral, non-toxic and pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture of the active ingredient (s) and inert carrier materials. Suitable binders can include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flowing lactose, beta-lactase, and corn sweeteners, synthetic and natural gums, such as acacia, tragacanth or sodium alginate, carboxy-methyl-ethylene glycol, polyalkylene glycol, waxes , sodium croscarmalosa, and the like. 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 formulation is that described in the U.S.A. 5,358,941, which is incorporated herein by reference. The compounds used in the present method can also be coupled with soluble polymers as marketable drug vehicles. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide and the like. The studies that were carried out in accordance with this invention selected patients based on their diminished BMD of the spine, comparatively with the general population, and not a history of a frequent vertebral fracture. This was done to more closely represent the general osteoporotic population. Thus, these patients were at a lower risk of experiencing incidental vertebral fracture than patients typically grouped into endpoint fracture tests. Quite clinical endpoints were evaluated in the course of this invention, such as: Stature. - Height loss is a recognized clinical consequence of vertebral fractures. As a result of vertebral fractures due to osteoporosis, a patient may lose 10 to 20 cm for several years. The loss of height is due to collapse and vertebral kyphosis, which produce decreased mobility and compression of the abdominal and thoracic cavities. The measurement of height is a simple, economical, easily repeatable, radiation-free and highly repeatable procedure. Importantly, height is a continuous variable rather than categorical, and provides more possibility to detect differences between treatment groups. Although some variations of height in individual patients may reflect changes in posture or space of the intervertebral discs unrelated to the osteoporoeis, the comparison of the average changes within the treatment groups in a blinded, randomized, and Controlled by placebo, it provides an accurate assessment of the effect of alendronate on vertebral fractures. It was found that alendronate significantly reduces the average reduction observed in height, compared to placebo (p = 0.005). The non-electric and individual analyzes of the slope were also significant (p = 0.003 and p = <; 0.001, respectively). All analytical approaches indicate that the rate of height loss decreases with treatment with alendronate, and to a greater extent after three (as opposed to two) years of therapy. In addition, the average decreases observed in patients treated with placebo with an incidental vertebral fracture were substantially greater than those in similar patients treated with alendronate. Patients who suffered at least one vertebral fracture lost an average of 23.3 m in height in the placebo group, versus 5.9 m in the alendronate group. This marked difference implies that alendronate decreases not only the number of patients with incidental fractures, but also decreases the average number of fractures and the average severity of fractures. Therefore, a further aspect of this invention is a method to reduce the severity of fractures in patients who suffer a fracture by administering alendronate for a substantial period before fracture. Vertebral Fractures. - Calculations of frequent and incidental categorical vertebral fractures were made by comparing the height of the vertebrae of baseline of each patient with a reference population (frequent fracture) and with the follow-up of their heights (incidental fractures). Only data from the real baseline lines were used to determine frequent fractures. Any height relationship of the vertebrae of more than three standard deviations below their corresponding reference value of the population was defined as a frequent vertebral fracture. An incidental fracture was defined as greater than, or equal to, a 20% reduction in the vertebral height of the baseline, with an absolute reduction of at least 4 rnrn at any vertebral height between the baseline and the follow-up. After three years of treatment, the reduction observed in vertebral fractures is both statistically significant (p = 0.034) and clinically important [48%; 95% of I.C. = (72%, 5%) .7. The reduction of vertebral fracture was consistent through multiple analysis of the sgroup, including by study, dose, age (< or 2. 65 years) and stratification in the presence or absence of a frequent vertebral fracture. Spinal deformity .- The index of spinal deformity (SDI) was calculated for each patient as described in Minne et al., 1988, Bone and Min. 3: 335-349, which is incorporated in the present invention. as reference. Each individual vertebral height is divided by the corresponding height of the patient's fourth thoracic vertebra (T4) (anterior, middle or posterior) to generate a maximum of 39 vertebral height relationships. T4 was selected as the reference height because it rarely fractures and can be used to adjust the differences in the patient's height, as well as for differences in focal distances between the baseline and the follow-up (which could artificially alter the apparent sizes of the vertebral bodies between the time points). Each of the height relationships is then compared with the normal values of the population, and for those ratios that fall below the minimum normal value of the population, the absolute distances below the normal value are summed to express the total SDI. When SDT was used as a continuous measure of vertebral deformity, 41% of patients treated with placebo showed progression in the deformity, versus 33% of patients treated with alendronate (p = 0.028). Additionally, there was a significant difference in the limit (p = 0.054) in the distribution of SDI changes between the two groups. Also surprisingly, in accordance with this invention, it was shown that the effect of reducing the risk of vertebral fracture is the same for elderly patients (at least 65 years of age) and not elderly (age less than 65). years). A) YesAnother aspect of this invention is a method for reducing the risk of vertebral fracture in elderly osteoporotic women by administering an effective amount of alendronate for a substantial period. In addition, it has been shown that reducing the risk of vertebral fractures due to treatment with alendronate increases with time. The following non-limiting examples are presented to better illustrate the invention.

EXAMPLE 1 Post-menopausal women who have a "low" density of minerals in bones of the lumbar spine, defined as a bone mineral density (BMD) less than, or equal to, 0.92 g / cm2 (+ or - 0.02 g / cm2) measured by the Lunar DPX method, or less than, or equal to, 0.80 g / cm2 (+ or -0.02 g / cm2), measured by the holographic 0DR method, is considered to have osteoporosis. This definition corresponds to a BMD of approximately two and a half standard deviations below the average BMD of mature pre-rnenopaeicae Caucasian women in the United States. Otherwise, patients enjoy good health based on medical history, a physical examination and an evaluation of laboratory analysis. Only 20% of the registered women had vertebral fractures on admission. Data were collected from a total of 881 patients from two study groups, following virtually identical procedures and protocol design, except that one study was conducted in the United States, and the other was conducted in Canada, Mexico, Europe, Israel, South America, Australia and New Zealand. The data of the two groups is grouped > Aron later. We treated 526 patients with alendronate, from one of the following oral dose regimens: A) 10 mg daily for three years; B) 5 rng for three years; or C) 20 ing for two years, followed by 5 g for one year. The 355 patients received placebo. Additionally, all patients received dietary evaluation and instruction on calcium intake. Almost all received calcium supplements to provide 500 g of elemental calcium (such as carbonate) to ensure nutritional adequacy. The evaluation of vertebral fracture and vertebral deformity (SÜI) is based on X-ray measurements of the lateral spine, blind to the sequence. The X-rays of the lateral spine were all in the baseline one, two, and three years. The X-ray reading procedure included a computerized record of the total measurements on of the vertebrae observed on X-rays, a procedure known as digitization. Six protruding points were observed on the bony process of vertebra, three along the upper edge and three along the lower edge of of the 14 vertebrae, from the fourth thoracic vertebra to the fifth lumbar vertebra. A computer network with grid threads is used to incorporate data co or X, Y coordinates into a commercially available computer software and digitization board, which calculates the distance between the protruding points (height of the vertebrae) in millimeters EXAMPLE 2 Categorical vertebral fracture 39 women of Example 1 had at least one new vertebral fracture during the three years of study, as determined from the height of their vertebrae. 22 of 355 (6.20%) women in the placebo group had a new vertebral fracture compared to 17 of 526 (3.23%) women in the alendronate group. This is a significantly lower amount (? = 0.034) in the group treated with alendronate. The relative risk of incidental fracture in patients treated with alendronate against patients treated with placebo was 0.52 (95% CI. = C0.28, 0.953). Additionally, the magnitude of the fracture reduction after three years is greater than that observed after two years of treatment. In addition, among patients who experienced at least one incidental vertebral fracture, the proportion of patients who experienced two or more fractures was much greater among patients treated with placebo (15/22, 68%) than those treated with alendronate (3 / 17, 18%). Due to the combination of fewer affected patients and fewer fractures per patient, the number of vertebral fractures per 100 patients was substantially lower in patients treated with alendronate (4.2) than those treated with placebo (11.3). Also, the. The group of women treated with alendronate, who suffered an incidental fracture, had less severe fractures than the group of women treated with placebo. Table I below shows the number of moderate fractures (classified as endplate deformity fractures) and severe fractures (wedge or compression fractures) in group. TABLE I Types of sustained fractures Placebo Alendronate Moderate Fractures 3/22 (13.6%) 6/17 (35.3%) Severe Fractures 19/22 (86.4%) 11/17 (64.7%) EXAMPLE 3 index of deformity of the spine The results of the changes in the index of deformity in the spine (SDI), calculated as described in the specification, are shown in Table I, below. 41% of women in the placebo group had an increase in vertebral deformity, compared with 33% of those in the group treated with alendronate (p = 0.028 by Chi-square test). This difference after 3 years is greater than that observed after 2 years (38% in the group treated with placebo, 33% in the group treated with alendronate). Overall, the average change from the baseline was 0.082 and 0.041 for the groups treated with placebo and with alendronate, respectively. In addition, for women with increased deformity, the average changes were 0.212 and 0.143 for the groups treated with placebo and with alendronate, respectively. The Uilcox rank-sum test resulted in a significant difference in the boundary line (p = 0.054) in the SDI change distribution from the baseline between the placebo and alendronate groups.

EXAMPLE 3 Height Height was measured in all patients using a Harpenden stage, which accurately measures height to the nearest rn and is the most accurate method available to date. Measurements of height were turned 3 times; if two of them varied by more than 4 mm, a fourth and a fifth measurements were taken. The average of the three (or five) measurements was used as the value of the stature. The average change in height after three years of treatment was - 4.61 rn for the group treated with placebo, and - 3.0.1 m for the group treated with alendronate, which is a significant difference (p = 0.005, 95 IC% = C0.49, 2.71 mm]). The difference after three years was greater than the effect observed only after two years (- 3.2 mrn for the placebo group, - 1.9 for the group treated with alendronate). In addition, a straight line was adjusted to the response profile over time of each individual to obtain an estimate of the slope for each individual. This is shown in figures 1 and 2.

Claims (24)

NOVELTY OF LR INVENTION CLAIMS

1. The use of an effective amount of alendronate or a pharmaceutically acceptable salt thereof to prepare compositions for reducing the risk of vertebral fractures in an osteoporotic woman.

2. The use according to claim 1, wherein the composition prepared is alendronate administered orally.

3. The use according to claim 2, wherein the administration is carried out in a dose is from 5 mg to 20 mg daily.

4. The use according to claim 3, wherein the administration of the prepared composition of alendronate is carried out substantially daily for a period of at least 2 years.

5. The use according to claim 3, wherein the administration of the prepared composition of alendronate is carried out substantially daily for a period of at least 3 years.

6. The use according to claim 1, wherein the woman is of advanced age.

7. The use of an effective amount of alendronate to prepare compositions for reducing the severity of a fracture in patients suffering a fracture, by administering them for a substantial period before the fracture.

8. The use according to claim 7, wherein the prepared composition of alendronate is administered orally.

9. The use according to claim 8, wherein the administration is carried out in a dose of 5 g to 20 rng daily.

10. The use according to claim 9, wherein the prepared composition of alendronate is administered substantially during a period of at least 2 years.

11. The use according to claim 9, wherein the prepared composition of alendronate is administered substantially daily for a period of at least 3 years.

12. The use according to claim 7, wherein the woman is of advanced age.

13. The use of an effective amount of alendronate to prepare compositions for reducing the deformity of the spine in osteoporotic women, by administering them for a substantial period.

14. The use according to claim 7, wherein the prepared composition of alendronate is administered orally.

15. The use according to claim 8, wherein the administration is carried out in a dose of 5 rng to 20 g daily.

16. The use according to claim 9, wherein the prepared composition of alendronate is administered substantially for a period of at least 2 years.

17. The use according to claim 9, wherein the prepared composition of alendronate is administered substantially daily for a period of at least 3 years.

18. The use according to claim 7, wherein the woman is of advanced age.

19. The use of an effective amount of alendronate to prepare compositions for reducing the deformity of the spine in osteoporotic women, administering them for a substantial period.

20. The use according to claim 7, wherein the prepared composition of alendronate is administered orally.

21. The use according to claim 8, wherein the administration is carried out in a dose of 5 g to 20 mg daily.

22. The use according to claim 9, wherein the prepared composition of alendronate is substantially administered for a period of at least 2 years.

23. The use according to claim 9, wherein the prepared composition of alendronate is administered substantially daily for a period of at least 3 years.

24. The use according to claim 7, wherein the woman is of advanced age.