HRP960080A2 - Method of lessening the risk of vertebral and other fractures - Google Patents
Method of lessening the risk of vertebral and other fractures Download PDFInfo
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- HRP960080A2 HRP960080A2 HRP960080A HRP960080A2 HR P960080 A2 HRP960080 A2 HR P960080A2 HR P960080 A HRP960080 A HR P960080A HR P960080 A2 HRP960080 A2 HR P960080A2
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- Prior art keywords
- alendronate
- fractures
- vertebral
- years
- fracture
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Description
Ovaj se izum odnosi na postupak umanjivanja rizika prijeloma kralježnice i ostalih prijeloma kod žena u postmenopauzi putem primjene učinkovite količine bisfosfonata alendronata. This invention relates to a method of reducing the risk of vertebral fractures and other fractures in postmenopausal women through the administration of an effective amount of the bisphosphonate alendronate.
Područje tehnike The field of technology
Osteoporoza je metabolička bolest obilježena smanjivanjem koštane mase i jakosti koje je ovisno o dobi. Stanje prije svega zahvaća žene u postmenopauzi, iako se može javiti i u starijih muškaraca. Najučestalija klinička obilježja osteoporoze su prijelomi kralježnica, kuka i ručnog zgloba. Osteoporosis is a metabolic disease characterized by an age-dependent decrease in bone mass and strength. The condition primarily affects postmenopausal women, although it can also occur in older men. The most common clinical signs of osteoporosis are fractures of the spine, hip and wrist.
Prijelomi povezani s osteoporozom vrlo su učestali, pa se javljaju u oko 27 % žena iznad 65 godina života i oko 60 % žena iznad 80 godina života. Prijelomi kralježnice često ostanu nedijagnosticirani, iako su učestalo povezani s bolovima i mogu ograničiti bolesnikovu sposobnost za izvođenje dnevnih aktivnosti. Mnogostruki prijelomi kralježnice mogu dovesti do kifotičnog držanja, kronične boli u leđima i onesposobljenosti. Fractures related to osteoporosis are very common, occurring in about 27% of women over 65 years of age and about 60% of women over 80 years of age. Spinal fractures often remain undiagnosed, although they are often associated with pain and may limit the patient's ability to perform daily activities. Multiple spinal fractures can lead to kyphotic posture, chronic back pain, and disability.
Prijelomi povezani s osteoporozom vrlo su učestali, pa se javljaju u oko 27% žena iznad 65 godina života i oko 60% žena iznad 80 godina života. U žena koje trpe od osteoporoze prijelomi kuka su osobito učestali, pa se javljaju u čak 20% žena u postmenopauzi. Prijelomi kuka mogu imati vrlo ozbiljne posljedice - zabilježena je stopa smrtnosti iznad 20% unutar šest mjeseci od prijema u bolnicu. Fractures related to osteoporosis are very common, occurring in about 27% of women over 65 years of age and about 60% of women over 80 years of age. Hip fractures are particularly common in women suffering from osteoporosis, and occur in as many as 20% of postmenopausal women. Hip fractures can have very serious consequences - a mortality rate of over 20% has been reported within six months of hospital admission.
Brojna se sredstva danas koriste za sprečavanje i liječenje osteoporoze, uključujući hormonsko nadomjesno liječenje (estrogen), kalcitonin, etidronat (bisfosfonat), ipriflavon, fluorid, vitamin D i kalcij. Uspjesi liječenja su raznoliki. Iako je objavljeno da neka od gore spomenutih terapijskih sredstava mogu povećati gustoću minerala u kostima (BMD, bone mineral density), nije potvrđena povezanost između povećane BMD i smanjenja učestalosti bilo kralježničnih bilo nekralježničnih prijeloma. Premda je niska BMD povezana s učestalijim prijelomima, viša BMD nije nužno u svezi sa smanjenjem učestalosti prijeloma, poglavito nekralježničnih. Na primjer, za fluoride je pokazano da pospješuju BMD, ali učestalost prijeloma kuka također raste. A number of agents are used today to prevent and treat osteoporosis, including hormone replacement therapy (estrogen), calcitonin, etidronate (bisphosphonate), ipriflavone, fluoride, vitamin D, and calcium. Treatment successes are varied. Although it has been reported that some of the above-mentioned therapeutic agents can increase bone mineral density (BMD), the association between increased BMD and a reduction in the frequency of either vertebral or non-vertebral fractures has not been confirmed. Although low BMD is associated with more frequent fractures, higher BMD is not necessarily associated with a reduction in the frequency of fractures, especially non-vertebral fractures. For example, fluorides have been shown to improve BMD, but the incidence of hip fractures also increases.
Opis izuma Description of the invention
U skladu s ovim izumom, nađeno je da je primjena alendronata (4-amino-1-hidroksi-butiliden-1,1-bisfosfonata) korisna u umanjivanju rizika prijeloma kralježnice kao i ostalih prijeloma kod žena u postmenopauzi koje trpe od osteoporoze. Nadalje, umanjeni rizik je održan i čak dodatno umanjen prilikom dugoročne primjene alendronata. In accordance with the present invention, administration of alendronate (4-amino-1-hydroxy-butylidene-1,1-bisphosphonate) has been found to be beneficial in reducing the risk of vertebral fractures as well as other fractures in postmenopausal women suffering from osteoporosis. Furthermore, the reduced risk was maintained and even further reduced during long-term use of alendronate.
Ovaj izum opisuje postupak umanjivanja rizika prijeloma kralježaka primjenom terapijski učinkovite količine alendronata ili njegove farmaceutski prihvatljive soli na bolesnice koje trpe od osteoporoze. Drugi je predmet ovog izuma umanjivanje rizika od deformacije kralježnice primjenom terapijski učinkovite količine alendronata ili njegove farmaceutski prihvatljive soli tijekom dužeg vremenskog razdoblja. Slijedeći predmet ovog izuma je sprečavanje gubitka visine primjenom učinkovite količine alendronata ili njegove farmaceutski prihvatljive soli tijekom dužeg vremenskog razdoblja. Daljnji predmet ovog izuma je umanjivanje težine prijeloma kralježnice koji dožive takav prijelom primjenom alendronata tijekom dužeg vremenskog razdoblja prije nastupa prijeloma. Ovaj izum također sadrži postupak umanjivanja rizika nekralježničnih prijeloma primjenom učinkovite količine alendronata ili njegove farmaceutski prihvatljive soli na bolesnice koje trpe od osteoporoze. Daljnji predmet ovog izuma je umanjivanje rizika prijeloma kuka i/ili ručnog zgloba primjenom učinkovite količine alendronata ili njegove farmaceutski prihvatljive soli tijekom dužeg vremenskog razdoblja. Slijedeći predmet ovog izuma je uporaba alendronata ili njegove farmaceutski prihvatljive soli za pripravu lijeka korisnog za umanjivajne rizika prijeloma kralježnice. Daljnji je predmet ovog izuma uporaba alendronata ili njegove farmaceutski prihvatljive soli za pripravu lijeka korisnog za umanjivanje rizika nekralježničnih prijeloma. This invention describes a method of reducing the risk of vertebral fracture by administering a therapeutically effective amount of alendronate or a pharmaceutically acceptable salt thereof to patients suffering from osteoporosis. Another object of the present invention is to reduce the risk of spinal deformity by administering a therapeutically effective amount of alendronate or a pharmaceutically acceptable salt thereof over a long period of time. Another object of the present invention is to prevent height loss by administering an effective amount of alendronate or a pharmaceutically acceptable salt thereof over an extended period of time. A further object of the present invention is to reduce the severity of spinal fractures that experience such a fracture by administering alendronate for an extended period of time prior to the onset of the fracture. The present invention also includes a method of reducing the risk of non-vertebral fractures by administering an effective amount of alendronate or a pharmaceutically acceptable salt thereof to patients suffering from osteoporosis. A further object of the present invention is to reduce the risk of hip and/or wrist fracture by administering an effective amount of alendronate or a pharmaceutically acceptable salt thereof over an extended period of time. Another object of the present invention is the use of alendronate or a pharmaceutically acceptable salt thereof for the preparation of a medicament useful for reducing the risk of spinal fractures. A further object of this invention is the use of alendronate or a pharmaceutically acceptable salt thereof for the preparation of a medicament useful for reducing the risk of non-vertebral fractures.
Ustanovilo se, neočekivano, da se učestalost prijeloma kralježaka može umanjiti primjenom učinkovite količine alendronata tijekom dužeg vremenskog razdoblja. Smanjenje, rizika procijenjeno je na najmanje oko 40%, vjerojatnije barem oko 45% ili još vjerojatnije, barem oko 48 %; ovaj se pad rizika pokazao statistički značajan u usporedbi s placebom. Kada se promatra ukupan broj prijeloma kralježnice (kao broj bolesnika s prijelomom), alendronat postiže umanjivanje rizika prijeloma kralježnice najmanje oko 50%, vjerojatnije barem oko 60% ili još vjerojatnije barem oko 63% na 100 bolesnika u usporedbi s placebom. Pored toga, alendronat postiže statistički značajno usporavanje napredovanja deformacija kralježnice u usporedbi s bolesnicima koji su liječeni placebom. Nadalje, stopa rizika prijeloma kralježnice (u usporedbi s placebom) je manja nakon tri godine primjene nego nakon jedne ili dvije godine. It was found, unexpectedly, that the incidence of vertebral fractures can be reduced by using an effective amount of alendronate over a longer period of time. The risk reduction was estimated to be at least about 40%, more likely at least about 45% or even more likely at least about 48%; this reduction in risk was found to be statistically significant compared to placebo. When looking at the total number of vertebral fractures (as the number of patients with a fracture), alendronate achieves a reduction in the risk of vertebral fracture of at least about 50%, more likely at least about 60%, or even more likely at least about 63% per 100 patients compared with placebo. In addition, alendronate achieves a statistically significant slowing of the progression of spinal deformities compared to patients treated with placebo. Furthermore, the risk rate of vertebral fracture (compared to placebo) is lower after three years of use than after one or two years.
Također je, u skladu s ovim izumom, pokazano da je porast gustoće minerala u kostima koji je uočen uz primjenu alendronata u pozitivnoj svezi sa smanjivanjem učestalosti prijeloma kralježnice, smanjenjem deformacija kralježnice i zadržavanjem visine. It has also been shown, in accordance with the present invention, that the increase in bone mineral density observed with the use of alendronate is positively associated with a reduction in the frequency of spinal fractures, a reduction in spinal deformities and height retention.
Ovo upućuje na zaključak da alendronat tijekom dugotrajne primjene osim što smanjuje resorpciju kosti ima i pozitivan učinak na proizvodnju jače kosti. Također se, u skladu s ovim izumom, neočekivano pokazalo da se učestalost nekralježničnih prijeloma može smanjiti primjenom učinkovite količine alendronata tijekom dužeg vremenskog razdoblja. Smanjenje rizika nekralježničnih prijeloma procijenjeno je na najmanje oko 20%, vjerojatnije barem oko 25% ili još vjerojatnije barem oko 29% u usporedbi s placebom. Osobito iznenađuje da je apsolutni rizik nekralježničnih prijeloma (u usporedbi s placebom) manji nakon tri godine primjene nego nakon jedne ili dvije godine. This leads to the conclusion that alendronate during long-term use, in addition to reducing bone resorption, also has a positive effect on the production of stronger bone. Also, in accordance with the present invention, it has unexpectedly been shown that the incidence of non-vertebral fractures can be reduced by administration of an effective amount of alendronate over a long period of time. The reduction in risk of non-vertebral fractures was estimated to be at least about 20%, more likely at least about 25%, or even more likely at least about 29% compared to placebo. It is particularly surprising that the absolute risk of non-vertebral fractures (compared to placebo) is lower after three years of use than after one or two years.
Također je, u skladu s ovim izumom, pokazano da je porast gustoće minerala u kostima koji je uočen uz primjenu alendronata u pozitivnoj svezi sa smanjivanjem učestalosti nekralježničnih prijeloma. Ovo upućuje na zaključak da alendronat, kada se primjenjuje tijekom daljeg vremenskog razdoblja, ne samo što smanjuje brzinu kojom se kost resorbira, već i pozitivno djeluje na stvaranje jače kosti. Also, in accordance with this invention, it has been shown that the increase in bone mineral density observed with the use of alendronate is positively related to the reduction in the frequency of non-vertebral fractures. This suggests that alendronate, when administered over a longer period of time, not only reduces the rate at which bone is resorbed, but also has a positive effect on the formation of stronger bone.
Žene koje primaju alendronat u skladu s ovim izumom trpe od osteoporoze, tj. imaju gustoću minerala u kostima (BMD) dvije, ili dvije i pol standardne devijacije ispod prosjeka žena prije menopauze. Women receiving alendronate in accordance with the present invention suffer from osteoporosis, i.e., have a bone mineral density (BMD) two, or two and a half standard deviations below the average of premenopausal women.
Opis slika Description of images
Slika 1 je grafikon koji pokazuje o vremenu ovisan profil smanjivanja visine svih bolesnica u placebo i alendronatnoj skupini. Obilježena je srednja promjena ± standardna pogreška. Figure 1 is a graph showing the time-dependent height reduction profile of all patients in the placebo and alendronate groups. Mean change ± standard error is indicated.
Slika 2 je grafikon koji pokazuje o vremenu ovisan profil smanjivanja visine bolesnica koje su tijekom ispitivanja doživjele prijelom kralježaka. Označena je srednja promjena ± standardna pogreška. Figure 2 is a graph showing the time-dependent profile of height reduction in patients who experienced a vertebral fracture during the study. Mean change ± standard error is indicated.
Slika 3 je grafikon koji pokazuje kumulativnu funkciju preživljavanja u vremenu do prve pojave nekralježničnog prijeloma, što je izračunato pomoću postupka sa životnim tablicama, kao što je opisano u Primjeru 6. Podaci predstavljaju pulirani rezultat pet zasebnih kliničkih ispitivanja. Nakon, tri godine, razlike nastale kao posljedica liječenja su statistički značajne. Figure 3 is a graph showing the cumulative survival function of time to the first occurrence of a non-vertebral fracture, as calculated using the life table procedure, as described in Example 6. The data represent the pooled result of five separate clinical trials. After three years, the differences resulting from the treatment are statistically significant.
U objašnjenjima i zahtjevima vrijede slijedeće definicije za korištene pojmove: In the explanations and requirements, the following definitions apply to the terms used:
“Učinkovita količina” znači najmanje onu količinu koja je potrebna za postizanje umanjivanja rizika prijeloma, ali je manja od toksične količine. "Effective amount" means at least the amount necessary to achieve a reduction in the risk of fracture, but less than the toxic amount.
“Dulje vremensko razdoblje” znači vrijeme dovoljno dugo da omogući kostima bolesnika onoliko povećanje gustoće minerala (BMD) i čvrstoće koje ih čini otpornijima na prijelome. Tipično dulje vremensko razdoblje je dugačko, trajanja barem dvije godine, povoljno je dulje od dvije godine, a još povoljnije dulje od tri godine. "Longer period of time" means time long enough to allow the patient's bones to increase in bone mineral density (BMD) and strength enough to make them more resistant to fracture. Typically, a longer period of time is long, lasting at least two years, preferably longer than two years, and even more favorably longer than three years.
“Uzastopno dnevno” znači da se primjena namjerava provoditi svakodnevno, ali bolesnik može povremeno nenamjerno preskočiti dozu, pri čemu ukupan učinak nije različit od onog kad bolesnik svakodnevno prima dozu. "Consecutive daily" means that administration is intended to be done daily, but the patient may occasionally inadvertently skip a dose, with the overall effect being no different than when the patient receives a daily dose.
“Stariji” se odnosi na dob jednaku ili veću od 65 godina života "Senior" refers to age equal to or greater than 65 years of age
“Mlađi” se odnosi na dob manju od 65 godina života. "Younger" refers to an age less than 65 years of age.
“PYR” znači godine rizika osobe, a računaju se zbrajanjem vremena tijekom ispitivanja za svakog bolesnika tijekom kojeg je došlo do prvog nekralježničnog prijeloma ili do završetka pokusa, ovisno o tome što se dogodilo prije. “PYR” stands for person-years at risk, and is calculated by adding the time during the trial for each patient during which the first non-vertebral fracture occurred or until the end of the trial, whichever occurred first.
Alendronat se može pripraviti bilo kojim od postupaka opisanih u SAD patentnoj prijavi br. 5019651, 4992007 i WO 95/06052 (objavljeno 2 ožujka 1995) koje su ovdje uključene kao reference. Farmaceutski prihvatljive soli alendronata uključuju soli alkalijskih kovina (npr., Na, K), zemnoalkalijskih kovina (npr., Ca), soli neorganskih kiselina kao što je HCl i soli organskih kiselina kao što su limunska kiselina i aminokiseline. Preporučuju se oblici s natrijevim solima, poglavito trihidratni oblik mononatrijske soli. Alendronate can be prepared by any of the procedures described in US patent application no. 5019651, 4992007 and WO 95/06052 (published Mar. 2, 1995) which are incorporated herein by reference. Pharmaceutically acceptable salts of alendronate include salts of alkali metals (eg, Na, K), alkaline earth metals (eg, Ca), salts of inorganic acids such as HCl, and salts of organic acids such as citric acid and amino acids. Forms with sodium salts are recommended, especially the trihydrate form of the monosodium salt.
Spojevi ovog izuma mogu se primijeniti peroralnim oblicima kao što su tablete, kapsule (svaka od kojih ima svojstvo produljenog otpuštanja ili vremenski proračunatog otpuštanja), pilula, prašaka, zrnaca, eliksira, pasti, tinktura, suspenzija, sirupa i emulzija. Ovisno o obliku, primjena se vrši intravenski (u bolusu ili infuziji), intraperitonejski, supkutano ili intramuskularno, korištenjem oblika koji su dobro poznati prosječnim poznavateljima farmaceutske struke. Učinkovita ali neotrovna količina željenog spoja može se koristiti za sprečavanje prijeloma. Preporuča se da bolesnici primaju alendronat uzastopno dnevno tijekom dužeg vremenskog razdoblja da bi učinak bio zamjetan. The compounds of the present invention can be administered in oral forms such as tablets, capsules (each of which have sustained release or timed release properties), pills, powders, granules, elixirs, pastes, tinctures, suspensions, syrups and emulsions. Depending on the form, administration is carried out intravenously (in a bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, using forms that are well known to the average pharmaceutical expert. An effective but non-toxic amount of the desired compound can be used to prevent fractures. It is recommended that patients receive alendronate consecutively daily for a long period of time for the effect to be noticeable.
To znači da bolesnik treba primati alendronat barem polovinu dana u razdoblju liječenja, s time da razdoblje liječenja traje barem jednu godinu, a uputno je i duže - dvije, tri ili više godina. U shemi koja se preporučuje, bolesnik prima alendronat uzastopno dnevno tijekom najmanje tri godine u svrhu postizanja najboljeg učinka. Predvidivo je da će tijekom tako dugotrajnog liječenja bolesnik imati i razdoblja kada neće uzimati lijek; no, kako alendronat ima dug aktivni život u kostima i ovo je uzeto u obzir uz uvjet da bolesnik prima alendronat barem polovinu dana u prethodnom šestomjesečnom razdoblju. Također, ovaj izum obuhvaća i primjenu alendronata kliničkim režimom, tj. bolesnik može primati alendronat određeno vremensko razdoblje (na primjer, jedan dan, tjedno, mjesečno, polumjesečno ili tijekom nekoliko mjeseci), nakon toga se alendronat ukine (mogu se ali ne moraju u tom razdoblju davati dodatne tvari za poticanje koštane izgradnje ili sprečavanje koštane razgradnje i/ili hormonalno liječenje) tijekom jednog razdoblja (u istom ili različitom trajanju od razdoblja primjene), da bi se nakon toga ponovno uvelo liječenje alendronatom. This means that the patient should receive alendronate for at least half of the days during the treatment period, with the treatment period lasting at least one year, and preferably longer - two, three or more years. In the recommended regimen, the patient receives alendronate consecutively daily for at least three years in order to achieve the best effect. It is predictable that during such a long-term treatment, the patient will have periods when he will not take the medicine; however, as alendronate has a long active life in bones, this was taken into account with the condition that the patient received alendronate at least half of the day in the previous six-month period. Also, this invention includes the use of alendronate in a clinical regimen, i.e. the patient can receive alendronate for a certain period of time (for example, one day, weekly, monthly, semi-monthly or for several months), after which the alendronate is discontinued (may or may not be in during that period, give additional substances to stimulate bone building or prevent bone breakdown and/or hormonal treatment) during one period (in the same or different duration than the period of application), in order to re-introduce alendronate treatment afterwards.
Režim doziranja ovog načina liječenja izabire se ovisno o različitim činiteljima uključujući dob, težinu, spol i medicinsko stanje bolesnika, težinu stanja koje se liječi, put primjene, funkciju bubrega i jetre, kao i osobitosti upotrijebljenog spoja ili njegove soli. Prosječno vješt liječnik ili kliničar moći će brzo odrediti i propisati učinkovitu količinu lijeka potrebnu da bi se spriječili prijelomi kostiju. The dosage regimen of this method of treatment is selected depending on various factors including the age, weight, gender and medical condition of the patient, the severity of the condition being treated, the route of administration, kidney and liver function, as well as the characteristics of the compound or its salt used. A physician or clinician of average skill will be able to quickly determine and prescribe the effective amount of medication needed to prevent bone fractures.
Peroralno doziranje ovog izuma, kada se koristi za sprečavanje prijeloma kostiju, kretat će se od 0.05 mg po kg tjelesne težine na dan (mg/kg/dan) do oko 1.0 mg/kg/dan. Preporučene peroralne doze za ljude mogu se kretati oko 2.5-5 mg/dan ukupne dnevne doze tijekom razdoblja liječenja. Oral dosage of this invention, when used to prevent bone fractures, will range from 0.05 mg per kg of body weight per day (mg/kg/day) to about 1.0 mg/kg/day. Recommended oral doses for humans may range from 2.5-5 mg/day of the total daily dose during the treatment period.
Preporučeni raspon je 5-20 mg/dan, odnosno 5, 10 ili 20 mg/dan. Doze se lijekom vremena mogu mijenjati, tako da bolesnik može primiti visoku dozu, npr. 20 mg/dan tijekom dvije godine liječenja, nakon čega slijedi primjena niže doze, npr. 5 mg/dan. Slijedeći mogući način je primjena niske doze (npr. približno 5 mg) tijekom dužeg vremenskog razdoblja, čime se također postiže dobar učinak. Pripravci korišteni u ovom izumu mogu sadržavati 2.5-50 mg, s time da je preporučeni raspon 5-20 mg, odnosno pripravci od 5, 10 i 20 mg. The recommended range is 5-20 mg/day, i.e. 5, 10 or 20 mg/day. Doses can be time-shifted, so a patient can receive a high dose, eg 20 mg/day for two years of treatment, followed by a lower dose, eg 5 mg/day. Another possible way is to use a low dose (eg approximately 5 mg) over a longer period of time, which also achieves a good effect. The preparations used in this invention can contain 2.5-50 mg, with the recommended range being 5-20 mg, i.e. preparations of 5, 10 and 20 mg.
Alendronat se može primijeniti u jednoj dnevnoj dozi ili podijeljen u više doza. Poželjno je uzimanje bez hrane, najbolje 30 minuta do 2 sata prije o b r o ka, na pr. doručka, da bi se osigurala primjerena apsorpcija. Alendronate can be administered as a single daily dose or divided into several doses. It is preferable to take it without food, preferably 30 minutes to 2 hours before a meal, e.g. breakfast, to ensure adequate absorption.
U postupcima ovog izuma, aktivna tvar se tipično primjenjuje u smjesi s pogodnim farmaceutskim razrjeđivačima, ekscipijensima ili nosačima (koji su ovdje skupno nazvani “tvari nosači”), prikladno izabranima ovisno o načinu primjene, to jest peroralne tablete, kapsule, eliksiri, sirupi i slično, a u skladu s uobičajenim farmaceutskim postupcima. Na primjer, za peroralnu primjenu u obliku tablete ili kapsule, aktivni sastojak se može kombinirati s peroralnim, neotrovnim, farmaceutski prihvatljivim inertnim nosačem kao što je laktoza, škrob, saharoza, glukoza, metilceluloza, magnezijev stearat i slično: za peroralnu primjenu u tekućem obliku, peroralni sastojci lijeka mogu se kombinirati s bilo kojim peroralnim, neotrovnim, farmaceutski prihvatljivim inertnim nosačem kao što je etanol, glicerol, voda i slično. Nadalje, kada je to potrebno ili poželjno, u smjesu aktivnog sastojka i inertnih tvari nosača mogu se dodati i pogodne tvari za vezanje, lubrikansi, tvari za dezintegraciju i tvari za bojanje. Pogodne tvari za vezanje uključuju škrob, želatinu, prirodne šećere kao što je glukoza, bezvodna laktoza, laktoza slobodnog tijeka, beta-laktoza i kukuruzna sladila, prirodne i sintetičke gume kao što je akacija, tragakant ili natrijev alginat, karboksimetilceluloza, polietilenglikol, voskovi, cros karmaloza natrij i slično. Lubrikansi korišteni u ovim oblicima za doziranje uključuju natrijev oleat, natrijev stearat, magnezijev stearat, natrijev benzoat, natrijev acetat, natrijev klorid i slično. Osobito preporučljiva formulacija za tablete je ona opisana u SAD patentnoj prijavi br. 5358941, koja je ovdje uključena kao referenca. In the methods of the present invention, the active substance is typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (herein collectively referred to as "carriers"), appropriately selected depending on the route of administration, i.e., oral tablets, capsules, elixirs, syrups, and similarly, and in accordance with usual pharmaceutical procedures. For example, for oral administration in tablet or capsule form, the active ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, and the like: for oral administration in liquid form , the oral drug ingredients can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Furthermore, when necessary or desirable, suitable binders, lubricants, disintegrants and coloring agents can be added to the mixture of active ingredient and inert carrier substances. Suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flowing lactose, beta-lactose and corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, cros carmalose sodium and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. A particularly recommended tablet formulation is that described in US patent application no. 5358941, which is incorporated herein by reference.
Spojevi koji se koriste u ovom brzom postupku također se mogu vezati s topivim polimerima kao ciljnim nosačima lijeka. Takvi polimeri uključuju polivinilpirolidon, piran ko-polimer, polihidroksipropil-metakrilamid i slično. The compounds used in this rapid procedure can also be bound to soluble polymers as drug target carriers. Such polymers include polyvinylpyrrolidone, pyran co-polymer, polyhydroxypropyl methacrylamide and the like.
Prijelomi kralježnice Fractures of the spine
Ispitivanja koja su se bavila umanjivanjem rizika od prijeloma kralježnice a provedena su u skladu s ovim izumom, izdvojila su bolesnike na temelju njihove smanjene BMD kralježnice u usporedbi s općom populacijom bez spoznaja o prethodnim prijelomima kralježaka. Ovo je učinjeno u svrhu boljeg oslikavanja opće populacije s osteoporozom. Ti su bolesnici imali manji rizik incidentnog prijeloma kralježnice nego bolesnici koji se obično uključuju u pokuse o ishodima prijeloma. Vertebral fracture risk reduction trials conducted in accordance with the present invention have stratified patients based on their reduced spine BMD compared to the general population without knowledge of prior vertebral fracture. This was done in order to better represent the general population with osteoporosis. These patients had a lower risk of incident vertebral fracture than patients typically enrolled in fracture outcome trials.
Različiti su klinički parametri praćeni tijekom nastajanja ovog izuma, a neki od njih su: Various clinical parameters were monitored during the development of this invention, and some of them are:
VISINA - gubitak visine je priznate klinička posljedica prijeloma kralježnice. Kao rezultat prijeloma kralježnice zbog osteoporoze, bolesnik može izgubiti 10-20 cm u nekoliko godina. Gubitak visine nastaje zbog kolapsa kralježaka i kifoze, što dovodi do smanjene pokretljivosti i pritiska na trbušnu i prsnu šupljinu. Mjerenje visine je jednostavan, jeftin, lako i često ponovljiv postupak bez zračenja. Važno je da je visina više stalna nego kategorijska varijabla, pa njome uspješnije otkrivamo razlike između liječenih skupina. Iako pojedinačne varijacije u visini ponekih bolesnika mogu biti odraz promjena u držanju ili promjena prostora intervertebralnih diskova, što nije povezano s osteoporozom, usporedba prosječnih promjena unutar liječenih skupina u randomiziranom, slijepom ispitivanju kontroliranom placebom omogućava pravilnu procjenu učinka alendronata na prijelome kralježnice. Našlo se da alendronat značajno umanjuje uočeni pad visine u usporedbi s placebom, (p = 0.005). HEIGHT - loss of height is a recognized clinical consequence of spinal fractures. As a result of a spinal fracture due to osteoporosis, a patient can lose 10-20 cm in a few years. Loss of height occurs due to vertebral collapse and kyphosis, which leads to reduced mobility and pressure on the abdominal and thoracic cavity. Height measurement is a simple, inexpensive, easy and often repeatable procedure without radiation. It is important that height is a constant rather than a categorical variable, so we can more successfully detect differences between treated groups. Although individual variations in the height of some patients may reflect changes in posture or changes in intervertebral disc space, which are not related to osteoporosis, comparison of mean changes within treatment groups in a randomized, blinded, placebo-controlled trial allows a proper assessment of the effect of alendronate on vertebral fractures. Alendronate was found to significantly reduce the observed height loss compared to placebo, (p = 0.005).
Neparametrijske individualne analize nagiba također su pokazale značajnost (p=0.003, odnosno p<0.001). Svi analitički pristupi ukazuju da je brzina gubitka visine umanjena pomoću liječenja alendronatom, u još većem opsegu nakon tri (u usporedbi s dvije) godine liječenja. Non-parametric individual slope analyzes also showed significance (p=0.003, respectively p<0.001). All analytical approaches indicated that the rate of height loss was reduced by alendronate treatment, to an even greater extent after three (compared to two) years of treatment.
Nadalje, srednji pad uočen u bolesnika liječenih placebom koji su zadobili incidentni prijelom kralježnice bio je dugoročno veći od onog u sličnih bolesnika liječenih alendronatom. Bolesnici koji su doživjeli najmanje jedan prijelom kralježnice izgubili su u prosjeku 23.3 mm visine u placebo skupini, za razliku od 5.9 mm u skupini liječenoj alendronatom. Ova značajna razlika upućuje na to da alendronat, osim što smanjuje broj bolesnika s incidentnim prijelomima, smanjuje i prosječan broj prijeloma i prosječnu težinu prijeloma. Shodno tome, daljnji aspekt ovog izuma je postupak umanjivanja težine prijeloma u bolesnika koji dožive prijelom primjenom alendronata tijekom dužeg vremenskog razdoblja prije prijeloma. Furthermore, the mean decline observed in placebo-treated patients who sustained an incident vertebral fracture was greater in the long-term than that observed in similar patients treated with alendronate. Patients who experienced at least one vertebral fracture lost an average of 23.3 mm in height in the placebo group, compared to 5.9 mm in the alendronate group. This significant difference suggests that alendronate, in addition to reducing the number of patients with incident fractures, also reduces the average number of fractures and the average severity of fractures. Accordingly, a further aspect of the present invention is a method of reducing fracture severity in patients who experience a fracture by administering alendronate for an extended period of time prior to the fracture.
PRIJELOMI KRALJEŽNICE - Izračunavanje prevalentnih i incidentnih kategorijskih prijeloma kralježnice izvedeno je usporedbom početne vrijednosti visine kralježaka svakog bolesnika s referentnom populacijom (prevalentni prijelom) i s njezinim kontrolnim visinama (incidentni prijelom). Samo podaci pravih početnih vrijednosti korišteni su za određivanje prevalentnih prijeloma. Svaki omjer visine kralježnice veći od tri standardne devijacije ispod referentne vrijednosti odgovarajuće populacije označen je kao prevalentni prijelom kralježnice. Incidentnim prijelomom smatrano je svako smanjenje osnovne vrijednosti visine kralježnice jednako ili veće od 20%, s apsolutnim smanjenjem od najmanje 4 mm u bilo kojoj visini kralježaka između početne vrijednosti i praćene vrijednosti. SPINE FRACTURES - Calculation of prevalent and incident categorical spine fractures was performed by comparing the initial value of the vertebral height of each patient with the reference population (prevalent fracture) and with its control heights (incident fracture). Only true baseline data were used to determine the prevalence of fractures. Any vertebral height ratio greater than three standard deviations below the reference value of the corresponding population was designated as a prevalent vertebral fracture. An incident fracture was considered any decrease in baseline vertebral height equal to or greater than 20%, with an absolute decrease of at least 4 mm in any vertebral height between baseline and follow-up.
Nakon tri godine liječenja, uočeno smanjenje prijeloma kralježnice je i statistički značajno (p = 0.034) i klinički važno [48%; 95% C.I. = (72%, 5%)]. Smanjenje učestalosti prijeloma kralježaka bilo je prisutno u analizi brojnih podskupina, sastavljenih prema ispitivanju, dozi, dobi (< ili > 65 godina) i stratifikaciji ovisno o prisutnosti ili odsutnosti prevalentnog prijeloma kralježnice. After three years of treatment, the observed reduction in spine fractures is both statistically significant (p = 0.034) and clinically important [48%; 95% C.I. = (72%, 5%)]. A reduction in the incidence of vertebral fractures was present in a number of subgroup analyses, stratified by trial, dose, age (< or > 65 years) and stratified by the presence or absence of prevalent vertebral fracture.
DEFORMACIJA KRALJEŽNICE - indeks deformacije kralježnice (SDI, Spine Deformity Index) izračunat je za svakog bolesnika na način opisan u Minne i sur., 1988, Bone and Min. 3:335-349, koji je ovdje uključen kao referenca. Svaka pojedina visina kralješka podijeljena je s odgovarajućom visinom bolesnikovog četvrtog prsnog kralješka (T4) (prednja, srednja ili stražnja) u svrhu dobivanja maksimuma omjera visina 39 kralježaka. T4 je izabran kao referentna visina jer rijetko podliježe prijelomu i može poslužiti za usklađivanje razlika u visinama bolesnika, kao i razlika u fokalnoj udaljenosti filma između početne vrijednosti i kontrole (koja može umjetno promijeniti prave veličine tijela kralježaka između točaka u vremenu). Svaki je od omjera visine potom uspoređen s normama populacije, te su omjerima koji su se našli ispod minimuma populacijske norme zbrojene apsolutne udaljenosti od te norme čime je dobiven ukupni SDI. Uz uporabu SDI kao kontinuirane mjere deformacije kralježnice, 41% bolesnika koji su primali placebo pokazalo je napredovanje deformacije, nasuprot 33% bolesnika koji su primali alendronat (p = 0.028). Pored toga, nađena je granično značajna razlika (p = 0.054) u raspodjeli promjena SDI između dvije skupine. SPINE DEFORMITY - the Spine Deformity Index (SDI) was calculated for each patient in the manner described in Minne et al., 1988, Bone and Min. 3:335-349, which is incorporated herein by reference. Each individual vertebral height was divided by the corresponding height of the patient's fourth thoracic vertebra (T4) (anterior, middle, or posterior) to obtain the maximum height ratio of the 39 vertebrae. T4 was chosen as the reference height because it is rarely subject to fracture and can be used to accommodate differences in patient heights as well as differences in film focal distance between baseline and control (which can artificially alter true vertebral body sizes between time points). Each of the height ratios was then compared with the population norms, and with the ratios that were below the minimum of the population norm, the absolute distances from that norm were added, resulting in the total SDI. Using the SDI as a continuous measure of spinal deformity, 41% of patients receiving placebo showed progression of deformity, versus 33% of patients receiving alendronate (p = 0.028). In addition, a marginally significant difference (p = 0.054) was found in the distribution of SDI changes between the two groups.
Također je, u skladu s ovim izumom, neočekivano nađeno da je učinak umanjivanja rizika prijeloma kralježnice jednak kod starijih (najmanje 65 godina života) kao i kod mladih (dob manja od 65 godina) bolesnica. U svezi s tim, daljnji je predmet ovog izuma postupak umanjivanja rizika prijeloma kralješka u starijih žena koje trpe od osteoporoze primjenom učinkovite količine alendronata tijekom dužeg vremenskog razdoblja. Also, in accordance with this invention, it was unexpectedly found that the effect of reducing the risk of spinal fracture is the same in elderly (at least 65 years of age) as in young (age less than 65 years) patients. Accordingly, a further object of the present invention is a method of reducing the risk of vertebral fracture in elderly women suffering from osteoporosis by administering an effective amount of alendronate over an extended period of time.
Nadalje, pokazano je da umanjivanje rizika prijeloma kralježnice postignuto liječenjem alendronatom raste s vremenom. Furthermore, it has been shown that the reduction in the risk of vertebral fracture achieved by treatment with alendronate increases over time.
Nekralježnični prijelomi Non-vertebral fractures
Kombinirana analiza pet kliničkih pokusa pokazuje da alendronat, kada se primjenjuje tijekom dužeg vremenskog razdoblja, može umanjiti rizik nekralježničkih prijeloma. Na primjer, kod bolesnika koji su primali alendronat procijenjena kumulativna incidencija prijeloma nakon tri godine bila je 9%, a ukupna brzina porasta incidencije nekralježničnih prijeloma bila je 3.26 na 100 PYR. Nasuprot tome, kod bolesnika koji su primali placebo, procijenjena kumulativna incidencija nakon tri godine bila je 12.6%, a ukupna brzina porasta incidencije nekralježničnih prijeloma bila je 4.45 na 100 PYR. Procjena ukupnog smanjenja rizika nekralježničnih prijeloma pomoću životnih tablica (proporcionalni modeli rizika) iznosi 29% uz 95%-tni interval pouzdanosti (0.3%, 49.8%), p-vrijednost povezana s opaženim smanjenjem rizika bila je p = 0.048. Analiza brzina dala je istovjetne p-vrijednosti uz sličan interval pouzdanosti. A combined analysis of five clinical trials shows that alendronate, when administered over a long period of time, can reduce the risk of non-vertebral fractures. For example, in patients receiving alendronate, the estimated cumulative incidence of fractures at three years was 9%, and the overall rate of increase in the incidence of non-vertebral fractures was 3.26 per 100 PYR. In contrast, in patients receiving placebo, the estimated cumulative incidence at three years was 12.6%, and the overall rate of increase in the incidence of non-vertebral fractures was 4.45 per 100 PYR. The estimate of the overall risk reduction of non-vertebral fractures using life tables (proportional hazard models) was 29% with a 95% confidence interval (0.3%, 49.8%), the p-value associated with the observed risk reduction was p = 0.048. Analysis of rates yielded identical p-values with similar confidence intervals.
Pored toga, učinak umanjivanja rizika nekralježničnih prijeloma je jednak za starije (najmanje 65 godina života) kao i za mlade (dob manja od 65 godina) bolesnice. U svezi s tim, daljnji je predmet ovog izuma postupak umanjivanja rizika nekralježničnih prijeloma u starijih žena koje trpe od osteoporoze primjenom učinkovite količine alendronata tijekom dužeg vremenskog razdoblja. In addition, the effect of reducing the risk of non-vertebral fractures is the same for elderly (at least 65 years of age) as for young (age less than 65) patients. Accordingly, a further object of the present invention is a method of reducing the risk of non-vertebral fractures in elderly women suffering from osteoporosis by administering an effective amount of alendronate over an extended period of time.
Nadalje, pokazano je da umanjivanje rizika nekralježničnih prijeloma postignuto liječenjem alendronatom raste s vremenom. Furthermore, the reduction in the risk of non-vertebral fractures achieved with alendronate treatment has been shown to increase over time.
Slijedeći neograničavajući primjeri izloženi su u svrhu boljeg prikazivanja izuma. The following non-limiting examples are set forth in order to better illustrate the invention.
Primjer 1 Example 1
Ispitivanje prijeloma kralješka Vertebral fracture examination
Za žene u postmenopauzi koje imaju nisku gustoću minerala u lumbalnoj kralježnici, koja je određena kao BMD manja ili jednaka 0.92 g/cm2 (+ ili - 0.02 g/cm2) mjereno prema Lunar DPX metodi ili kao manja ili jednaka 0.80 g/cm2 (+ ili -0.02 g/cm2) mjereno prema Hologic QDR metodi, smatrano je da imaju osteoporozu. Ova je definicija u skladu s vrijednostima BMD od približno dvije i pol standardne devijacije ispod srednje vrijednosti BMD zdravih predmenopauzalnih bijelkinja u SAD. Bolesnice su inače su dobrog zdravlja, što je procijenjen o anamnestički, fizikalnim pregledom i orijentacijskim laboratorijskim testovima. Samo je 20% uključenih žena imalo prijelome kralježnice na početku. For postmenopausal women who have low mineral density in the lumbar spine, which is defined as 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 according to the Hologic QDR method, they were considered to have osteoporosis. This definition is consistent with BMD values approximately two and a half standard deviations below the mean BMD of healthy premenopausal white women in the US. The patients are otherwise in good health, as assessed by anamnestic, physical examination and orientation laboratory tests. Only 20% of the women included had spinal fractures at baseline.
Podaci su prikupljeni na ukupnom broju od 881 bolesnice iz dvije ispitivane skupine (kohorte), koje su podvrgnute praktički istovjetnom protokolu i postupcima, osim što je jedno ispitivanje provedeno u SAD, a drugo u Kanadi, Meksiku, Evropi, Izraelu, Južnoj Americi, Australiji i Novom Zelandu. Podaci dobiveni iz obje skupine su pulirani. 526 bolesnica liječeno je alendronatom, prema jednom od slijedećih režima peroralnog doziranja: A) 10 mg dnevno tijekom tri godine; B) 5 mg tijekom tri godine; i C) 20 mg tijekom dvije godine i potom 5 mg tijekom jedne godine. 355 bolesnica primalo je placebo. Pored toga, sve su bolesnice primile upute o prehrani i unosu kalcija. Gotovo su sve dobivale 500 mg dodatnog elementarnog kalcija (u obliku karbonata) da bi se osigurao odgovarajući dnevni unos. Data were collected on a total of 881 patients from two study groups (cohorts), who were subjected to practically the same protocol and procedures, except that one study was conducted in the USA, and the other in Canada, Mexico, Europe, Israel, South America, Australia and New Zealand. Data obtained from both groups were pooled. 526 patients were treated with alendronate, according to one of the following oral dosing regimens: A) 10 mg per day for three years; B) 5 mg during three years; and C) 20 mg for two years and then 5 mg for one year. 355 patients received placebo. In addition, all patients received instructions on nutrition and calcium intake. Almost all received 500 mg of additional elemental calcium (in the form of carbonate) to ensure adequate daily intake.
Procjena prijeloma i deformacije kralježnice (SDI) temeljena je na mjerenjima lateralnog radiograma kralježnice, analiziranih u slijedu. Lateralni radiogram kralježnice učinjen je na početku, nakon jedne, dvije i nakon tri godine. U postupku očitavanja radiograma korišteno je kompjutorski unos mjera svakog pojedinog kralješka s radiograma - postupak poznat kao digitalizacija. Određeno je šest točaka na koštanom nastavku svakog kralješka, tri na gornjem i tri na donjem rubu svakog od 14 kralježaka, i to od četvrtog prsnog do petog lumbalnog kralješka. Korišten je kompjutorski miš za unos podataka kao što su X,Y koordinate u komercijalno dostupnu digitalizacijsku ploču i kompjutorski program, koji obračunava udaljenosti između zadanih točaka (visine kralježaka) u milimetrima. The assessment of spinal fracture and deformity (SDI) is based on the measurements of the lateral radiograph of the spine, analyzed in sequence. A lateral radiograph of the spine was taken at the beginning, after one, two and three years. In the process of reading the radiogram, computer input of the measurements of each individual vertebra from the radiogram was used - a procedure known as digitalization. Six points were determined on the bony extension of each vertebra, three on the upper and three on the lower edge of each of the 14 vertebrae, from the fourth thoracic to the fifth lumbar. A computer mouse was used to enter data such as X,Y coordinates into a commercially available digitizing board and a computer program, which calculates the distances between given points (vertebrae heights) in millimeters.
Primjer 2 Example 2
Kategorijski prijelom kralješka Categorical vertebral fracture
Trideset i devet žena iz Primjera 1 zadobilo je najmanje jedan novi prijelom kralježnice tijekom tri godine ispitivanja, što je procijenjeno iz njihove visine. Dvadeset i dvije od 355 (6.20 %) žena u placebo skupini zadobilo je novi prijelom kralježnice nasuprot 17 od 526 (3.23%) žena u skupini liječenoj alendronatom. Ovo predstavlja značajno manji broj (p = 0,034) u skupini liječenoj alendronatom. Thirty-nine women from Example 1 sustained at least one new vertebral fracture during the three years of the study, as estimated from their height. Twenty-two of 355 (6.20%) women in the placebo group sustained a new vertebral fracture versus 17 of 526 (3.23%) women in the alendronate group. This represents a significantly lower number (p = 0.034) in the alendronate group.
Relativni rizik incidentnog prijeloma kralježnice u skupini liječenoj alendronatom u odnosu na skupinu koja je primala placebo bio je 0.52 (95%C.I. = [0.28, 0.95]). Pored toga, vrijednost umanjenja prijeloma je veća nakon tri nego nakon dvije godine liječenja. The relative risk of incident vertebral fracture in the alendronate group compared to the placebo group was 0.52 (95%C.I. = [0.28, 0.95]). In addition, the fracture reduction value is greater after three than after two years of treatment.
Nadalje, među bolesnicama koje su doživjele najmanje jedan incidentni prijelom kralježnice, udio onih koje su doživjele dva ili više prijeloma bio je daleko viši među bolesnicama koje su primale placebo (15/22; 68%) nego među onima koje su primale alendronat (3/17; 18%). Kao posljedica kombinacije manjeg broja zahvaćenih bolesnica i manjeg broja prijeloma po bolesnici, broj prijeloma kralježnice na 100 bolesnica bio je značajno niži u skupini liječenoj alendronatom (4.2) nego u onoj liječenoj placebom (11.3). Furthermore, among patients who experienced at least one incident vertebral fracture, the proportion of those who experienced two or more fractures was far higher among patients receiving placebo (15/22; 68%) than among those receiving alendronate (3/ 17; 18%). As a result of the combination of fewer affected patients and fewer fractures per patient, the number of spinal fractures per 100 patients was significantly lower in the alendronate-treated group (4.2) than in the placebo-treated group (11.3).
Osim toga, skupina žena liječenih alendronatom koje su doživjele incidentni prijelom imala je manje teške prijelome od žena liječenih alendronatom. Tablica 1 pokazuje broj blagih prijeloma (obilježenih kao prijelomi s deformacijom završne ploče) i teških prijeloma (prijelomi s drobljenjem ili klinasti prijelomi) u svakoj skupini. In addition, the group of alendronate-treated women who experienced an incident fracture had fewer severe fractures than the alendronate-treated women. Table 1 shows the number of mild fractures (labeled as endplate deformity fractures) and severe fractures (compression fractures or wedge fractures) in each group.
Tablica 1 Table 1
Tipovi nastalih prijeloma Types of resulting fractures
[image] [image]
Primjer 3 Example 3
Indeks deformacije kralježnice Spine deformation index
Rezultati promjena indeksa deformacije kralježnice (SDI), koji je izračunat i opisan u specifikaciji, izražen je u Tablici 1. 41% žena u placebo skupini imalo je porast deformacije kralježnice, u usporedbi s 33% u alendronatnoj skupini (p = 0.028 prema δ2 testu. Ova je razlika nakon tri godine promatranja postala veća od one koja je opažena nakon dvije godine (38% placebo; 33%. alendronat). The results of changes in the spinal deformity index (SDI), which was calculated and described in the specification, are shown in Table 1. 41% of women in the placebo group had an increase in spinal deformity, compared to 33% in the alendronate group (p = 0.028 according to the δ2 test .This difference after three years of observation became greater than that observed after two years (38% placebo; 33%. alendronate).
Ukupno, srednja promjena od početne vrijednosti bila je 0.082 za placebo, odnosno 0.041 za alendronatnu skupinu. Wilcoxov rank sum test pokazao je graničnu značajnost (p = 0.054) razlike u raspodjeli promjene u SDI u odnosu na početnu vrijednost uz placebo odnosno alendronat. Overall, the mean change from baseline was 0.082 for the placebo and 0.041 for the alendronate group. The Wilcox rank sum test showed borderline significance (p = 0.054) of the difference in the distribution of the change in SDI compared to the initial value with placebo or alendronate.
Primjer 4 Example 4
Visina Height
Visina je mjerena kod svih bolesnica korištenjem stadiometra po Harpendenu, koji precizno mjeri visinu do najbližeg milimetra i do danas je najtočnija postojeća metoda. Height was measured in all patients using the Harpenden stadiometer, which precisely measures height to the nearest millimeter and is the most accurate existing method to date.
Mjerenje visine provedeno je tri puta: ako su se bilo koja dva mjerenja razlikovala za više od 4 mm, provelo se i četvrto i peto mjerenje. Prosjek tri (odnosno pet) mjerenja korišten je kao vrijednost visine. Height measurement was performed three times: if any two measurements differed by more than 4 mm, a fourth and fifth measurement was also performed. The average of three (or five) measurements was used as the height value.
Srednja promjena visine nakon tri godine liječenja bila je -4.61 cm u placebo skupini i 3.01 mm u skupini liječenoj alendronatom, što je značajna razlika (p = 0.005, 95% C.I. = [0.49, 2.71 mm]). Razlika nakon tri godine bila je veća od učinka opaženog nakon samo dvije godine (-3.2 mm za placebo; -1.9 za alendronat). The mean change in height after three years of treatment was -4.61 cm in the placebo group and 3.01 mm in the alendronate group, a significant difference (p = 0.005, 95% C.I. = [0.49, 2.71 mm]). The difference after three years was greater than the effect observed after only two years (-3.2 mm for placebo; -1.9 for alendronate).
Nadalje, povučena je ravna crta za svaki pojedini profil reakcije u vremenu da bi se dobila procjena nagiba za svakog pojedinca. Ovo je prikazano na Slikama 1 i 2. Furthermore, a straight line was drawn for each individual response profile over time to obtain an estimate of the slope for each individual. This is shown in Figures 1 and 2.
Primjer 5 Example 5
Ispitivanja nekralježničnih prijeloma Investigations of non-vertebral fractures
Za žene u postmenopauzi koje imaju nisku gustoću minerala u lumbalnoj kralježnici, koja je određena kao BMD manja ili jednaka 0.92 g/cm2 (+ ili - 0.02 g/cm2) mjereno prema Lunar DPX metodi ili kao manja ili jednaka 0,80 g/c m 2 (+ ili -0.02 g/cm2) mjereno prema Hologic QDR metodi, smatrano je da imaju osteoporozu. Ova je definicija u skladu s vrijednostima BMD od približno dvije i pol standardne devijacije ispod srednje vrijednosti BMD zdravih premenopauzalnih bijelkinja u SAD. Bolesnice su inače dobrog zdravlja, što je procijenjeno anamnestički, fizikalnim pregledom i orijentacijskim laboratorijskim testovima. For postmenopausal women who have low mineral density in the lumbar spine, defined as 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 2 (+ or -0.02 g/cm2) measured according to the Hologic QDR method, they were considered to have osteoporosis. This definition is consistent with BMD values approximately two and a half standard deviations below the mean BMD of healthy premenopausal white women in the US. The patients are otherwise in good health, which was assessed by anamnestic, physical examination and orientation laboratory tests.
Podaci su prikupljeni na 1602 bolesnice iz pet ispitivanih skupina (kohorti). 1012 bolesnica liječeno je alendronatom, prema jednom od slijedećih režima doziranja: A) 5 mg dnevno tijekom dvije ili tri godine: B) 10 mg dnevno tijekom dvije ili tri godine; C) 20 mg tijekom dvije godine, nakon toga 5 mg tijekom jedne godine; D) 2.5 mg dnevno tijekom dvije godine; E) 40 mg dnevno tijekom tri mjeseca, nakon toga 2.5 mg dnevno tijekom 21 mjeseca; i F) 20 mg dnevno tijekom dvije godine. 590 bolesnica primalo je placebo. Uz to, sve su bolesnice primile upute o prehrani i unosu kalcija. Gotovo su sve dobivale 500 mg dodatnog elementarnog kalcija (u obliku karbonata) da bi se osigurao odgovarajući dnevni unos. Data were collected on 1602 patients from five examined groups (cohorts). 1012 patients were treated with alendronate, according to one of the following dosing regimens: A) 5 mg daily for two or three years: B) 10 mg daily for two or three years; C) 20 mg for two years, then 5 mg for one year; D) 2.5 mg per day for two years; E) 40 mg daily for three months, then 2.5 mg daily for 21 months; and F) 20 mg daily for two years. 590 patients received placebo. In addition, all patients received instructions on nutrition and calcium intake. Almost all received 500 mg of additional elemental calcium (in the form of carbonate) to ensure adequate daily intake.
Tablica 2 prikazuje broj bolesnica, broj nekralježničnih prijeloma i godine rizika osoba (PYR) liječenih skupina za svaku kohortu. Ukupan broj nekralježničnih prijeloma iznosio je 133: 60 u placebo skupini i 73 u alendronatnoj skupini. Ukupan broj nakupljenih PYR iznosio je 3587: 1347 u placebo skupini i 2240 u alendronatnoj skupini. Table 2 shows the number of patients, the number of non-vertebral fractures and the person-years at risk (PYR) of the treated groups for each cohort. The total number of non-vertebral fractures was 133: 60 in the placebo group and 73 in the alendronate group. The total number of accumulated PYR was 3587: 1347 in the placebo group and 2240 in the alendronate group.
Tablica 2 Table 2
Kombinirano ispitivanje nekralježničnih prijeloma i godina rizika osoba (PYR) Combined trial of non-vertebral fractures and person-years at risk (PYR)
[image] * ALEND znači “liječeni alendronatom” [image] * ALEND means "treated with alendronate"
Tablica 3 donosi stopu nekralježničnih prijeloma na 100 PYR liječene skupine svake od pet kohorti. U skupini placeba, stope su u rasponu od 2.34 do 10.38 nekralježničnih prijeloma na 100 PYR. Stope u alendronatnoj skupini kreću se između 0.78 i 6.04. Posljednji stupac Tablice 3 donosi tu stopu kao omjer prema placebu po kohortama. Omjeri su iznosili od 0.33 do 0.90 i potvrđuju da su za svaku kohortu omjeri u alendronatnim skupinama bez iznimke manji od onih u placebo skupini. Table 3 presents the rate of non-vertebral fractures per 100 PYR of the treated group of each of the five cohorts. In the placebo group, rates ranged from 2.34 to 10.38 nonvertebral fractures per 100 PYR. Rates in the alendronate group range between 0.78 and 6.04. The last column of Table 3 presents that rate as a ratio to placebo by cohort. The ratios ranged from 0.33 to 0.90 and confirm that for each cohort the ratios in the alendronate groups are without exception lower than those in the placebo group.
Tablica 3 Table 3
Kombinirano ispitivanje nekralježničnih prijeloma na 100 PYR Combined examination of non-vertebral fractures at 100 PYR
[image] [image]
Podaci su analizirani da bi se ustanovilo postoji li razlika u odgovorima između starijih (u dobi od 65 i više godina) i mlađih (u dobi do 65 godina) žena. Također je ispitan Coxov proporcionalni model rizika koji uključuje dob i liječenje kao efekte modela i protokol kao stratifikacijski činitelj. Dob se nije pokazala kao značajan činitelj bilo da je vrednovana kao kontinuirana varijabla bilo kao kategorijska vrijednost u svakom od modela. Relativni rizik bio je u oba modela gotovo istovjetan i iznosio je 1. To znači da nije bilo razlike u učinku na starije u odnosu na mlađe bolesnice. Rezultati su prikazani u Tablicama 4 i 5. The data were analyzed to determine if there was a difference in responses between older (aged 65 and over) and younger (under 65) women. A Cox proportional hazard model including age and treatment as model effects and protocol as a stratification factor was also examined. Age did not prove to be a significant factor whether it was evaluated as a continuous variable or as a categorical value in each of the models. The relative risk was almost the same in both models and amounted to 1. This means that there was no difference in the effect on older compared to younger patients. The results are presented in Tables 4 and 5.
Tablica 4 Table 4
Nekralježnični prijelomi u starijih Non-vertebral fractures in the elderly
[image] [image]
Tablica 5 Table 5
Nekralježnični prijelomi u mlađih Non-vertebral fractures in younger people
[image] [image]
Podaci su također analizirani i u svrhu procjene učinka godina liječenja. Rezultati su prikazani u Tablici 6. Data were also analyzed to assess the effect of years of treatment. The results are presented in Table 6.
Tablica 6 Table 6
Godišnja incidencija nekralježničnih prijeloma Annual incidence of non-vertebral fractures
[image] [image]
Primjer 6 Example 6
Izračunavanje pomoću životnih tablica Calculation using life tables
Kumulativne kliničke proporcije bez prijeloma i procjene intervala izračunate su uporabom metode životnih tablica za populacije pulirane protokolom; puliranje je učinjeno radi olakšavanja izlaganja podataka. Usporedbe između liječenja temeljene su na log rank statistici modela životnih tablica uz protokol kao stratifikacijski činitelj. Relativni je rizik izračunat korištenjem Coxovog modela proporcionalnih rizika za skupine podataka uz liječenje kao modelski učinak i protokol kao stratifikacijski činitelj. Slika 3 je prikaz kumulativne kliničke proporcije bez prijeloma. Razlike u kumulativnim proporcijama ovisne o liječenju povećane su u trećoj godini. Cumulative fracture-free clinical proportions and interval estimates were calculated using the life table method for protocol-pooled populations; pooling was done to facilitate data presentation. Comparisons between treatments were based on the log rank statistic of the life table model with protocol as a stratifying factor. The relative risk was calculated using the Cox proportional hazards model for the data groups with treatment as the model effect and protocol as the stratification factor. Figure 3 is a representation of the cumulative clinical proportion without fractures. Treatment-dependent differences in cumulative proportions increased in the third year.
Tablice 7 i 8 sažeto prikazuju statistiku modela životnih tablica za placebo i alendronatnu skupinu. Na kraju treće godine praćenja, procijenjena kumulativna proporcija bolesnica s kliničkim prijelomima bila je 0.090 u alendronatnoj skupini, a 0.126 u placebo skupini. Smanjenje rizika nekralježničnih prijeloma procijenjeno je na 29.3% uz 95%-tni interval pouzdanosti [0.3%, 49.8%], p-vrijednost povezana s ovom razlikom iznosi p = 0.047, Tables 7 and 8 summarize the life table model statistics for the placebo and alendronate groups. At the end of the third year of follow-up, the estimated cumulative proportion of patients with clinical fractures was 0.090 in the alendronate group and 0.126 in the placebo group. The reduction in the risk of non-vertebral fractures was estimated at 29.3% with a 95% confidence interval [0.3%, 49.8%], the p-value associated with this difference is p = 0.047,
Tablica 7 Table 7
Procjene preživljavanja pomoću životnih tablica puliranih skupina liječenih alendronatom Survival estimates using life tables of pooled alendronate-treated groups
[image] [image]
Tablica 8 Table 8
Procjene preživljavanja pomoću životnih tablica skupine liječene placebom Survival estimates using life tables of the placebo group
[image] [image]
Claims (9)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US39046295A | 1995-02-17 | 1995-02-17 | |
| US08/389,860 US20010051616A1 (en) | 1995-02-17 | 1995-02-17 | Method of lessening the risk of vertebral fractures |
| US41963195A | 1995-04-10 | 1995-04-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP960080A2 true HRP960080A2 (en) | 1997-10-31 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP960080 HRP960080A2 (en) | 1995-02-17 | 1996-02-16 | Method of lessening the risk of vertebral and other fractures |
Country Status (9)
| Country | Link |
|---|---|
| AR (1) | AR002707A1 (en) |
| CO (1) | CO4920257A1 (en) |
| CZ (1) | CZ259097A3 (en) |
| DZ (1) | DZ1991A1 (en) |
| HR (1) | HRP960080A2 (en) |
| IL (1) | IL117077A (en) |
| PE (1) | PE46197A1 (en) |
| TW (1) | TW453880B (en) |
| YU (1) | YU8896A (en) |
-
1996
- 1996-02-08 IL IL11707796A patent/IL117077A/en unknown
- 1996-02-12 PE PE00009596A patent/PE46197A1/en not_active Application Discontinuation
- 1996-02-13 CZ CZ972590A patent/CZ259097A3/en unknown
- 1996-02-14 DZ DZ960032A patent/DZ1991A1/en active
- 1996-02-14 AR ARP960101382A patent/AR002707A1/en not_active Application Discontinuation
- 1996-02-15 CO CO96007058A patent/CO4920257A1/en unknown
- 1996-02-16 YU YU8896A patent/YU8896A/en unknown
- 1996-02-16 HR HRP960080 patent/HRP960080A2/en not_active Application Discontinuation
- 1996-02-28 TW TW085102340A patent/TW453880B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| PE46197A1 (en) | 1997-11-28 |
| IL117077A0 (en) | 1996-06-18 |
| DZ1991A1 (en) | 2002-07-20 |
| CO4920257A1 (en) | 2000-05-29 |
| CZ259097A3 (en) | 1997-11-12 |
| YU8896A (en) | 1999-12-27 |
| TW453880B (en) | 2001-09-11 |
| IL117077A (en) | 2002-08-14 |
| AR002707A1 (en) | 1998-04-29 |
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