MXPA97006277A - The use of alendronate to prepare compositions to reduce the risk of non-vertebrate bit fractures - Google Patents

Abstract

In the prepared composition of alendronate, a bisphosphonate, when administered daily for a substantial period, can reduce the rate of non-vertebral fractures, fractures in post-menopausal women

Description

THE USE OF ALENDRQNATO TO PREPARE COMPOSITIONS TO REDUCE THE RISK OF NON-VERTEBRAL BIRTH FRACTURES BRIEF DESCRIPTION OF THE INVENTION This invention relates to a method for reducing (1) risk of non-vertebrate bone fractures in breast cancer patients, by administering an effective amount <k-> london, </ b>, a phosphonate bis II) BACKGROUND OF THE INVENTION Osteoporosis is a viral disease characterized by a reduction in mass and re ection of the bone related to age. The condition mainly affects post-rnenopausal women, au that I can also affect older men. The most common clinical manifestations of osteoporosis are fractures of the vertebrae, hip and wrist. 0 Osteoporosis-related fractures are very common, occurring in approximately 71% of women older than 65 years of age and in approximately 60% of men more than 50 years old. Hip fractures are particularly common in women with osteoporosis, 5 occurring in up to 20% of post-tnenopausal women.

Hip fractures can have very serious consequences - mortality rates of up to 10% have been observed several months after hospitalization.A number of therapies are commonly used to prevent and treat osteoporosis. It includes the replacement of hormones (estrogen), caleinin, etidronate (a bis phosphonate), ipriflavone, fluoride, vitamin D, and calcium, the degree of varxai treatment worldwide, although it has been reported that some of the aforementioned treatment agents may increase the density of bone minerals (BMD), there is no established correlation between increased BMD and a reduction in non-vertebral fractures, while low BMD correlates with an increased fracture rate , a higher BMD does not necessarily correlate with a reduction in fractures, particularly with nonvertebral fractures.For example, it has been shown that fluoride increases BMD, but the The risk of hip fractures also increases.

DESCRIPTION OF THE INVENTION It has been found according to the invention that the administration of alendronate (4-arn? No-lh? Drox i -butii? Den-, 1-bisfo fonat o) is useful to reduce the risk of non-vertebral fractures in osteoporot women icas μost- enopáusí cas. In addition, no risk reduction is maintained or even reduced or the long-term administration of alendronate. Therefore, this invention provides a method for reducing the risk of non-vertebral fractures by administering an effective amount of ñndronate or a pharmaceutically acceptable salt thereof to osteoporotic women. Another object of this invention is to reduce the risk of fractures of the hip and / or of the wrist by administering an effective amount of alendronate or a -, to the pharmaceutically acceptable pharmaceutical thereof for a substantial period. It has surprisingly been found that the The incidence of nonvertebral 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 non-vertebral fractures is at least about 20%, preferably at least about 25%, and even more preferably about 29% comparatively with the group treated with placebo. Par- ticularly surprising is that the rate of risk for non-vertebral fractures (comparatively with placebo) is lower after t years of administration than after one or two years of treatment. It has also 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 non-vertebral fractures. This indicates that when administered for a substantial period, alendronate does not only decrease l < ? speed with which the bone is resorbed, but also acts positively to produce a reordered bone. Women who receive alendronate according to this invention suffer from osteoporosis, ie they have a mineral density of bone '' BMD) which is at least about two or two and a half standard deviations lower than the normal value of women pre-menopausí cas.

DESCRIPTION OF THE FIGURE Figure 1 is a graph that shows, as a function of time, the accumulated survival with respect to the first occurrence of non-vertebral fractures, calculated using the life table method, as described in example 2. The data is the combined result of five separate clinical studies. At the end of three years, the di erences related to the treatment are statistically significant. 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 decrease the risk of the fracture rate, but less than a toxic amount. "Substantial period" means an amount of time that is large enough to allow the patient's bones to have an increased bone mineral density (BMD) and an increased resistance thereof, so that they are more resistant to fractures. A typical substantial period »* s a long period, and exceeds the two < t, and preferably exceeds at least about three years. "Substantially on a daily basis" means that the administration is meant to be on a daily basis, but the patient may occasionally inadvertently skip l < These doses, so that the general effect is not different from that observed when a patient receives the dose "flatly. "Older" means that age is equal to, or greater than * 65 years of age. "No advanced age" means that age is less than hr > years. "PYR" means the elderly in risk, and it is calculated by multiplying the number of patients in a group by the number of years'-, of the test. Fl alendronate can be prepared in accordance with any of the procedures described in the U.S. Patents. 5,019,651, 4,992,007, and the application series of F.U.A. No. 08 / 286,151 filed August 4, 1994, each of which is incorporated herein by reference. The pharmaceutically acceptable salts of alendronate include alkali metal salts (eg, Na, K), salts of alkaline metals (eg, Ca), salts of inorganic acids, such as HC1 and salts of organic acids such as citric acid and ami oracids. The forms of sodium * are preferred, par ticularly the form of the hydroxide of 1 onosodium. 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), nt rapen toneal, subcutaneous or intramuscular, 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 scratches .. I pa < - the s e r e c e r i ng the alendronate substantially daily for a substantial period so that the effect is observable. This means that the patient receives alendronate for 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 the aiendronate is not administered; but since alendonate has a long-lasting active life in the bone, this is considered to be within the scope of l < -? 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, ie, one month, and then may not receive alendronate (and may or may not other agents inhibiting or promoting bone absorption, and / or hormonal therapy) are not administered during a second period and receiving alendronate therapy by voice. 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 g per l g of body weight per day frng / g / day) to about 1.0 rng / kg / day. Preferred oral doses in humans may vary from total target doses of approximately 2.5-50 mg / d during the effective period of treatment, and a preferred amount is 2.5, 5, 10 or 20 mg / day. The doses may vary over a period, so that a patient may receive a high dose, such as 20 mg / day for a period of treatment, such as two years, followed by a lower dose, such as 5 mg / day. later. 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 dose or in a divided dose. It is convenient for the dose to 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 form of adminis desired ration, 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 may be combined with an oral, non-toxic and pharmaceutically acceptable inert carrier such < lactose, starch, sucrose, glucose, methylglyceous, 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 may also be incorporated into the mixture of the active ingredient (s) and the 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, carboxnnet, cellulose , pol eti 1 englicoi, waxes, c rosea ria slab of sodium, and,? m? lares. 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 US patent. 5,358,941, which is incorporated herein by reference. The compounds used in the present invention can also be coupled with soluble polymers as remanent drug carriers. Said polymers may include polyvinylpyrrolidone, pyran copolymer, U) po11 hi drox i prop 1metacr11 a ida y s i rn 11ai * en The combined analysis of five clinical trials shows that alendronate, when administered over a substantial period, can reduce the risk of a non-vertebral fracture. For example, in patients receiving alendronate, the estimated cumulative incidence of fracture after three years was 9.0%, and the overall incidence rate for nonvertebral fractures was 1.26 per 100 people of age at risk (PYR). In contrast, for patients receiving placebo, the estimated cumulative incidence was 12.6% after three years, the overall rate of nonvertebral fractures per 100 PYR patients was 4.45. The value * of the life table (proportional risk model) of the general reduction of the risk for non-vertebral fractures was 29%, with a 95% confidence interval of (0.3%, 49.0%). The value of p associated with the reduction observed in the risk was -0.048. The analysis of the handles gave an identical p value and a similar confidence interval. Also surprisingly, the effect of reducing the risk of non-vertebral fracture is the same for elderly patients (at least 65 years of age) and not elderly (age less than 65 years). Thus, another aspect of this invention is a method for reducing the risk of non-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 nonvertebral fractures due to treatment with alendronate increases with time. The following non-limiting examples are presented to better illustrate the invention EXAMPLE 1 Post-rnenopausal women who have a "ba" mineral density in the bones of the lumbar spine, defined as a bone mineral density (BMD) lower than, say, 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 QDR method, is considered to have osteoporosis. This definition corresponds to a BMD of approximately two and average standard deviations per * below the average BMD of mature pre-rnenopausal Caucasian women in the United States. Otherwise, patients enjoy good health based on medical history, a physical examination and an evaluation of laboratory analysis. Data were collected from 1502 patients from five study groups. 1012 patients were treated with alendronate, from one of the following oral dose regimens: A) 5 rng daily for two or three years; B) 10 rng daily for two or three years; C) 20 rng for two years, followed by 5 ing for one year; D) 2.5 ng daily for two years; E) 40 ng daily for 3 months, followed by 2.5 mg daily for 21 months; or F) 20 rng daily for two years. The 590 patients received placebo. Additionally, all patients received dietary evaluation and instruction on calcium intake. Almost all received calcium supplements to provide 500 mg of elemental calcium (such as carbonate) to ensure neutrality. Table 1 shows the number of patients, the number of non-vertebral fractures and the number of elderly people in risk (PYR) per treatment group for each of the groups. The total number of non-vertebral fractures reported was 133: there were 60 in the group treated with placebo and 73 in the group treated with alendronate. The total number of PYR accumulated was 3587: 1347 in the group treated with placebo and 2240 in the groups treated with alendronate.

TABLE 1 Combined studies Non-vertebral fractures and number of elderly people at risk (PYR) GROUP CASES TREATED CASES TREATED N WITH PLACEBO PRY N WITH ALENDRONATE PYR # 1 31 3 49 93 8 161 # 2 192 21 486 286 28 720 # 3 205 17 529 311 17 R05 # 4 71 3 328 140 2 256 # 5 91 16 154 182 18 298 All 590 60 1347 1012 73 2240 Combined Table 2 below shows the rate of non-vertebral fractures per 100 PYRs per treatment group for each of the five groups. In the group treated with placebo, the rates ranged from 2.34 to 10.30 • nonvertebral fractures per 100 PYR. The rates in the group treated with alendronate ranged from 0.78 to 6.04. The last column of table 2 reports these rates as ratios against placebo per group. Relationships ranged from 0.33 to 0.90, and confirm that for each of the groups, the rates in the alendronate-treated groups were consistently lower than those in the placebo group.

TABLE 2 Combined etudes Non-vertebral fractures per 100 PYR GROUP PLACE DO TREATED WITH RFLATION OF ALENDRONATE RATES OF GROUPS TREATED WITH ALEN RON OR GROUPS TREATED WITH PLACEBO # 1 6.07 4.97 0.82 # 2 4.32 3.89 0.90 # 3 3.21 0.66 # 4 2.34 0.7B 0.3.3 # 5 10.38 6.04 0.58 All 4.45 3.26 0.73 Combined The data were analyzed to determine * if there was a difference between the response between elderly women (65 years of age or older) and not elderly (age less than 65 years). We also examined the proportional hazards model of Cox that included age as well as treatment as effects of the model, and the protocol as a stratification factor, age was not a significant value if we evaluated co or a continuous variable or horn. a categorical value in any of the models. The estimated relative risk in both models was identical to 1. This means that there is no difference in the effect in elderly patients versus those of advanced age. The results are shown below in Tables 3 and 4.

TABLE 3 Non-Vertebral Fractures in the Elderly Placebo Treatments with Alendronate Risk Reduction N 284/9 C os 34 37 PYR 636 1036 15 Tension 14.6% 9"4% 36% Accumulated a ffrr aaccttuurraa 5, .355 3.57 33% per * 100 PYR TABLE 4 Non-vertebral fractures in non-elderly people 0 Placebo Treatments with risk reduction Alendronate N 306 533 Cases 26 36 PYR 711 1204 Í0 Incidence 10.8% 8.5% 21% Accumulated a a of fractures 3.66 2.99 18% * 5 per * 100 PYR The data were also analyzed for the effect of the years of treatment. The results are shown below in table 5 ,.

TABLE 5 Annual incidence of non-vertebral fractures Year of study Placebo Trados with Ratio of alendronate-treated groups with alendronate / placebo-treated groups 4 4.8888 3 3..5533 0.72 4.09 3.60 0.88 4.2? 2.12 0.50 TABLE 6 Only groups treated with alendronate The observed versus expected number of non-vertebral fractures by study time Year of study Observed Expected * Observed / Expected 1 3 333 4 466..88 0.71 30 41.5 0.72 10 15.2 0.66 * The number of cases expected in the group treated with alendronate, assuming no effect of the treatment.

EXAMPLE 2 Calculations of life tables Interval values and cumulative fracture-free clinical ratios were calculated using the life tables method for the combined populations on the protocol; This combination was made to facilitate the presentation. The comparisons in re treatments were based on the log of the ranks statistics of a life table model, with the protocol being a stratification factor. The relative risk was calculated using a Cox proportional hazards model for the pooled data, with the treatment being the effect of the model and the protocol the stratification factor. Figure 1 is the graph of the cumulative clinical proportion free of fractures. The differences related to treatment in accumulated proportions increase in the third year. Tables 7 and 8 below show the summary statistics for the life table model for the groups treated with alendronate and with placebo, respectively. At the end of three years of follow-up, the estimated cumulative proportion of patients with clinical fracture was 0.090 in the group treated with alendronate and 0.126 in the group treated with placebo. It was estimated that the risk reduction from non-vertebral fractures is 29.3% with a 95% confidence interval of I "0.3%, 49.8%"! The p-value with this difference is p 0.047.

TABLE 7 SURVIVAL VALUES OF THE LIFE TABLE COMBINED GROUPS TREATED WITH ALENDRONATE Interval No. of fractures Number Probability Probability of Standard Error deses) non-vertebral censored sample effective failure acuiulada survival of accumulated survival 0-3 10 39 992.5 0 1.0000 D 3-6 8 22 952.0 0.0101 0.9899 0.00317 6-9 9 20 923.0 0.0184 0.9816 0.00430 9-12 6 18 895.0 0.0280 8.9720 0.00531 12-15 12 15 872.5 0.0345 0.9655 0.00590 -18 9 8 849.0 0.0478 0.9522 0.00696 18-21 5 10 831.0 0.0579 0.9421 0.00765 21-24 4 147 747.5 0.0835 0.9365 0.00802 24-27 3 184 578.0 0.0685 0.9315 0.00035 27-30 4 10 478.0 0.0734 0.9266 0.00877 -33 0 5 466.5 0.0811 0.9189 0.00951 33-36 3 283 322.5 0.0811 0.9189 0.00951 36-39 0 178 89.0 0.0897 0.9103 0.01060 TABLE 8 SURVIVAL VALUES OF THE LIFE TABLE GROUPS TREATED WITH PLACEBO Interval No. of fractures Number Size of Probability of Probability of (months) non-vertebral censored Standard error shows effective accumulated failure survival of accumulated survival 0-3 7 586.5 0 1.0000 3-6 12 570.0 0.0119 0.9881 0.00448 6-9 14 548.0 0.0275 0.9725 9-12 11 528.5 0.0400 0.9500 0.00817 12-15 13 512.5 0.0472 0.9528 0.00888 15-18 5 498.5 0.0565 8.9435 0.00971 18-21 9 488.5 0.0622 0.9378 0.01020 21-24 437.0 0.0699 0.9301 0.01080 24-27 69 351.3 0.0869 0.9131 0.01220 7-30 4 311.8 0.0973 0.9027 0.01310 0-33 0 305.6 0.1009 0.8911 0.01420 3-36 198 203.0 0.1177 0.8823 0.01490 6-39 102 51.0 0.1264 0.8736 0.01600

Claims (6)

NOVELTY OF THE 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 nonvertebral bone fractures in an osteoporotic woman.

2. The use according to claim 1, wherein the prepared composition of alendronate is administered for a substantial period.

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

4. The use according to claim 3, wherein the dose is 2.5 mg to 20 mg daily.

5. The use according to claim 4, wherein the dose is 10 mg daily.

6. The use according to claim 3, wherein the prepared composition of alendronate is administered substantially daily for a period of more than two years. . - The use according to claim 3, wherein the prepared composition of alendronate is administered substantially daily for a period of at least about 3 years: * '. > ü.- The use of community with claim 1, where the woman is elderly q. The use of an effective amount of alendronate or a pharmaceutically acceptable salt thereof to prepare compositions for reducing the risk of nonvertebral bone fractures in a post-ninopausal osteoporotic woman, comprising orally administering to the woman 2.5 to 20 mg of alendronate on a daily basis for a substantial period. 10. The use according to claim cation 9, where the woman is of advanced age.