Bisphosphonates: Farsamaynta Ficilka iyo Doorka Dhaqanka Kiliinikada

by lafdhabarta | Xanuun Chronic, Caafimaadka, Daraasaadka Cilmi-baarista, Daaweyn, Wellness

Bisfosphonates waa nooc ka mid ah dawooyinka/daawoyinka xannibaya luminta cufnaanta lafaha si loogu daweeyo cudurrada lafaha lafaha. Inta badan waxaa loo qoraa daawaynta lafo-jileecu. Bisphosphonates waxay leeyihiin laba kooxood oo phosphonate ah. Caddaymaha ayaa muujinaya inay yareeyaan suurtogalnimada jabka ee haweenka ka dambeeya menopausal ee qaba lafo-jileeca.

Unugyada lafaha waxa lagu sameeyaa dib-u-qaabayn joogto ah oo loo kaydiyo si loo helo dheellitiran, ama homeostasis, iyada oo loo marayo osteoblasts-ka oo dhaliya lafo iyo osteoclasts oo burburiya lafaha. Bisphosphonates waxay joojisaa dheefshiidka lafaha iyagoo ku dhiirigelinaya osteoclasts inay maraan apoptosis ama dhimashada unugyada.

Isticmaalka bisfosphonates waxaa ka mid ah ka hortagga iyo daaweynta osteoporosis, cudurka Paget ee lafaha, metastasis lafaha (oo leh ama aan lahayn hypercalcemia), multi myeloma, hyperparathyroidism asaasiga ah, osteogenesis imperfecta, dysplasia fibrous, iyo xaalado kale oo muujinaya jilicsanaanta lafaha. Ujeedada maqaalkan soo socdaa waa in laga wada hadlo habka ficilka iyo doorka ku leh daaweynta bukaan-socodka ee bifosphonates.

aan la taaban karin

Bisphosphonates waa wakiilada aasaasiga ah ee arsenal farmashiyaha hadda ka soo horjeeda lafo-beelka osteoclast-dhexdhexaadiya sababtoo ah osteoporosis, Cudurka Paget ee lafaha, malignancies metastatic ilaa lafaha, myeloma badan, iyo hypercalcemia ee malignancy. Marka lagu daro isticmaalka hadda la ansixiyay, bisphosphonates waxaa caadi ahaan loo qoraa ka hortagga iyo daaweynta noocyo kala duwan oo ah xaaladaha kale ee lafaha, sida cufnaanta lafaha hoose iyo osteogenesis imperfecta. Si kastaba ha noqotee, aqoonsiga dhowaan ee isticmaalka bisphosphonate wuxuu la xiriiraa xaaladaha pathologic oo ay ku jiraan osteonecrosis ee daanka ayaa xoojiyay heerka baarista ee isticmaalka baahsan ee hadda jira ee daaweynta biphosphonate. Isticmaalka ereyada muhiimka ah ee bisphosphonate iyo daaweynta kiliinikada ee raadinta suugaanta PubMed laga bilaabo Janaayo 1, 1998, ilaa Maajo 1, 2008, waxaan dib u eegeynaa fahamka hadda jira ee hababka ay bisphosphonates ku sameeyaan saameyntooda osteoclasts, ka wada hadlaan doorka bisphosphonates ee ku dhaqanka kiliinikada, oo muuji meelaha walaaca leh ee la xidhiidha isticmaalka bifosphonate.

Hordhac

Tan iyo markii ay soo bandhigeen waxqabadka kiliinikada in ka badan 3 sano ka hor, bisphosphonates ayaa si sii kordheysa loogu isticmaalay noocyo badan oo xanuunada lafaha ah. Bisphosphonates hadda waxaa loo isticmaalaa in lagu daweeyo xaaladaha kala duwan sida xanuunada lafaha dhaxalka ah ee carruurta, postmenopausal iyo lafo-jileeca-glucocorticoid (GIO), iyo lafaha lafaha ee bukaanada qaba malignancies. Bisphosphonates waxay ku siin kartaa faa'iido caafimaad oo la taaban karo xaaladaha taas oo isu dheelitir la'aanta u dhaxaysa samaynta lafaha dhexdhexaadinta osteoblast iyo dib-u-soo-celinta laf-dhabarka osteoclast-ku-dhex-dhexaadka ah waxay hoosta ka xariiqaysaa cudurrada; si kastaba ha ahaatee, ururka dhawaan la aqoonsaday ee isticmaalka bifosphonate ee leh xaaladaha cudurrada, oo ay ku jiraan dawladaha lafaha hooseeya ee leh natiijadu jajabyada pathologic, osteonecrosis ee daanka (ONJ), iyo korodhka dhacdooyinka fibrillation atrial, ayaa keenay baadhitaan dheeraad ah isticmaalka ballaaran ee hadda. daaweynta bisphosphonate.

Suugaanta PubMed laga bilaabo Jannaayo 1, 1998, ilaa Maajo 1, 2008, ayaa dib loo eegay iyadoo la adeegsanayo bifosphonate iyo ku-dhaqanka bukaan-socod ahaan ereyo raadin ah. Maqaallo dheeri ah oo aan lagu helin raadinta aasaasiga ah ayaa lagu aqoonsaday qiimeynta suugaanta lagu tixraacay maqaallada dib loo eegay. Waxaan soo bandhignaa xogta ku saabsan horumarinta bisphosphonates sida wakiilada daweynta, hababka la soo jeediyay ee ay wakiiladani ku sameeyaan saameyntooda, iyo doorarka hadda jira ee daaweynta biphosphonate ee daaweynta kiliinikada. Intaa waxaa dheer, waxaan wax ka qabaneynaa meelaha qaar ee welwelka laga qabo dhakhaatiirta waxaanan soo jeedineynaa qaar ka mid ah arrimaha hadda aan la xalin ee la xiriira isticmaalka biphosphonate.

Qaab-dhismeedka Kiimikada oo Saldhig u ah Dhaqdhaqaaqa Caafimaadka

Dhisme ahaan, bisfosphonates waa kiimikooyin degganaansho kiimikaad ah oo ka mid ah pyrophosphate inorganic (PPi), oo ah unug dabiici ah oo ka soo baxa kaas oo kooxaha 2 fosfat ay ku xiran yihiin esterification (Jaantus 1, A). Bini'aadamka dhexdiisa, PPi waxaa loo sii daayaa iyada oo ay ka soo jeedaan wax badan oo ka mid ah falcelinta jirka; sidaas darteed, waxaa si fudud loogu ogaan karaa unugyo badan, oo ay ku jiraan dhiigga iyo kaadida.1 Daraasadaha horudhaca ah ee laga soo bilaabo 1960-yadii ayaa muujiyay in PPi ay awood u leedahay in ay joojiso caleenta iyada oo la isku dhejinayo crystals hydroxyapatite, taasoo keentay fikradda ah in nidaaminta heerarka PPi ay noqon karto habka kaas oo macdanta lafaha lagu maamulo.2

Sida analooga dabiiciga ah ee PPi, bisphosphonates waxay leeyihiin xidhiidh aad u sarreeya ee macdanta lafaha sababtoo ah waxay ku xidhaan crystals hydroxyapatite. Sidaa awgeed, haynta qalfoofka bisfosphonate waxay kuxirantahay helitaanka meelaha lagu xidho hydroxyapatite. Bisphosphonates ayaa si gaar ah loogu daraa goobaha dib-u-qaabaynta lafaha firfircoon, sida caadiga ah waxay ku dhacdaa xaalado lagu garto isbeddelka lafaha degdega ah. Bisphosphonate oo aan lagu hayn qalfoofka ayaa si degdeg ah looga nadiifiyaa wareegga dhiigga iyadoo la soo saarayo kelyaha. Marka lagu daro awoodda ay u leeyihiin in ay joojiyaan calcification, bisphosphonates waxay xakameysaa burburka hydroxyapatite, taas oo si wax ku ool ah u xakameynaysa dib-u-celinta lafaha.3 Hantidan aasaasiga ah ee bisphosphonates waxay keentay u adeegsigooda sida wakiilada kiliinikada. Dhawaanahan, waxaa la soo jeediyay in bisphosphonates ay sidoo kale u shaqeyso si loo xaddido labadaba osteoblast iyo osteocyte apoptosis.4,5 Muhiimadda qaraabada ah ee shaqadan ee dhaqdhaqaaqa bisphosphonate hadda ma cadda.

Wax ka beddelka qaabdhismeedka kiimikada ee bisphosphonates waxay ballaarisay farqiga u dhexeeya xoojinta bisphosphonate ee waxtarka leh ee looga baahan yahay dhaqdhaqaaqa antiresorptive marka loo eego kuwa xakameynaya macdanta matrixka lafaha, taasoo ka dhigaysa wareegga wareegga dhammaan bisphosphonates hadda loo isticmaalo daaweynta kiliinikada oo firfircoon oo kaliya oo loogu talagalay joojinta dib-u-celinta qalfoofka .1 Sida ku cad Jaantuska 1, A, qaabka asaasiga ah ee bifosphonates wax yar ayuu ka duwan yahay PPI taas oo ah bisfosphonates ka kooban yahay kaarboon dhexdhexaad ah oo aan biyo lahayn; kooxaha fosfooraska ee garab taagan kaarboonkan dhexe waa la ilaaliyaa. Sida lagu faahfaahiyay Jaantuska 1, B, oo ka duwan PPi, ku dhawaad ​​dhammaan bifosphonates ee isticmaalka kiliinikada ee hadda jira sidoo kale waxay leeyihiin koox hydroxyl ah oo ku xiran kaarboonka dhexe (oo lagu magacaabo booska R1). Kooxaha fosfooraska ee garabka ayaa bixiya bisfosphonates oo leh xiriir xooggan oo loogu talagalay kiristaalo hydroxyapatite ee lafaha (iyo sidoo kale waxaa lagu arkaa PPi), halka motif hydroxyl uu sii kordhinayo awoodda bisphosphonate ee lagu xiro calcium. Si wada jir ah, kooxaha fosfooraska iyo hydroxyl waxay abuuraan heer jaamacadeed halkii ay ka ahaan lahaayeen isdhexgalka laba-geesoodka ah ee u dhexeeya biphosphonate iyo matrixka lafaha, iyagoo siinaya bisfosphonates gaarkooda lafaha.1

Inkasta oo fosfooraska iyo kooxaha hydroxyl ay lagama maarmaan u yihiin bisfosphonate affinity ee matrixka lafaha, qaybta ugu dambeysa ee qaab dhismeedka (ee booska R2) ee ku xiran kaarboonka dhexe waa go'aaminta aasaasiga ah ee awoodda bisphosphonate ee xakameynta dib-u-celinta lafaha. Joogitaanka kooxda nitrogen ama amino waxay kordhisaa awoodda bisphosphonate ee antiresorptive 10 ilaa 10,000 marka loo eego bilowga hore ee aan nitrojiinka ku jirin bisphosphonates, sida etidronate.1,6 Daraasadihii ugu dambeeyay (oo lagu sifeeyay ka dib) ayaa qeexaya habka molecular ee nitrogen- oo ay ku jiraan bisphosphonates waxay joojiyaan dhaqdhaqaaqa osteoclast.

Sifada farmasiga ee muhiimka ah ee dhammaan bifosphonates waa xidhiidhkooda aadka u sarreeya, oo ka dhasha, lafaha marka loo eego unugyada kale. Xidhiidhka sare ee macdanta lafaha waxay u ogolaataa bisfosphonates si ay u gaaraan feejignaan sare oo maxalli ah oo dhan qalfoofka oo dhan. Sidaa awgeed, bisfosphonates waxay noqdeen daaweynta asaasiga ah ee xanuunka lafaha ee lagu garto dib-u-qaabaynta qalfoofka xad-dhaafka ah ama dheellitirka, taas oo hawlaha osteoclast iyo osteoblast aan si adag loo xirin, taasoo keentay in lafaha dhexdhexaadka ah ee osteoclast-dhexdhexaad ah.

Bisfosphonates hore oo aan nitrojiin ku jirin (etidronate, clodronate, iyo tiludronate) (Jaantuska 1, B) ayaa loo arkaa bisfosphonates jiilka kowaad. Sababtoo ah isku ekaanshaha qaabdhismeedkooda ee PPi, bisfosphonates aan nitrojiin ku jirin ayaa lagu daraa molecules of adenosine triphosphate (ATP) oo dhawaan la sameeyay fasalka II aminoacyl�transfer RNA synthetases ka dib markii osteoclast-dhexdhexaadin ka soo qaadashada dusha macdanta lafta.1 Intracellular accumulation. Analoog-yadan ATP-da aan-hydrolyzable-ka ahayn waxaa la rumeysan yahay inay yihiin cytotoxic ilaa osteoclasts sababtoo ah waxay joojiyaan hababka gacanta ee ATP-ku-tiirsanaanta badan, taasoo keenta apoptosis osteoclast.

Si ka duwan bisfosphonates hore, bisfosphonates jiilka labaad iyo saddexaad (alendronate, risedronate, ibandronate, pamidronate, iyo zoledronic acid) waxay leeyihiin nitrogen-ka kooban R2 silsilado dhinaca (Jaantus 1, C). Habka ay bisfosphonates ka kooban nitrogen ay kor u qaadaan apoptosis osteoclast waa ka duwan yahay bisfosphonates-ka aan nitrojiinka ku jirin. Sida xarrago leh ee lagu muujiyey daraasadihii dhawaa, bisfosphonates-ka ku jira nitrogen waxay isku xiraan oo joojiyaan dhaqdhaqaaqa farnesyl pyrophosphate synthase, enzyme muhiim ah oo xakameynaya dariiqa mevalonic acid ee muhiimka u ah soo saarista kolestaroolka, sterols kale, iyo isoprenoid lipids6,7 (Jaantus 2, A) analoogu waxay u badan tahay inay si toos ah u shaqeyso awoodda bisphosphonates si ay si xushmad leh ugu hoggaansamaan oo lagu hayo lafaha ka hor inta aan la helin endocytosis gudaha osteoclasts inta lagu jiro osteoclast-dhexdhexaadinta macdanta lafaha iyo dheef-shiidka matrixka (Jaantus 2, B). Marka la eego xaqiiqda ah in ku dhawaad ​​​​dhammaan bukaannada ay hadda helayaan daawaynta bisfosphonates-ka nitrogen ee xoogga badan halkii ay ka ahaan lahaayeen bisfosphonates hore oo aan nitrojiin ku jirin, inta ka hartay dib u eegistani waxay diiradda saaraysaa fasalkan cusub ee bifosphonates.

Tilmaamo Caafimaad oo Dheeraad ah

Inkasta oo bisfosphonate dhexdhexaadinta dhexdhexaadinta osteoclast apoptosis aan si toos ah loo qiyaasi karin gudaha goobta bukaan-socodka, hoos u dhigista ku-meel-gaadhka ah ee calaamadaha biochemical ee dib-u-soo-celinta lafaha (sida amino-iyo carboxyl-terminal burburka alaabta nooca 1 kolajka ee serum iyo kaadida) ka dib bilawga bisphosphonate ayaa loo tixgeliyaa. beddelka macquulka ah ee la isku halayn karo ee waxtarka iyo awoodda bisphosphonate. Cadaadiska ugu badan ee dib-u-soo-celinta lafuhu waxay dhacdaa qiyaastii 3 bilood gudahood bilawga daaweynta bisfosphonate afka ee la bixiyo maalin kasta, toddobaadle, ama bille waxayna sii ahaanaysaa qiyaas ahaan joogto ah iyadoo la sii wado daaweynta. daaweynta bisphosphonate.

Sida laga yaabo in la saadaaliyo, dhererka xakamaynta inta badan waa shaqada awoodda bisphosphonate ee isku-xidhka macdanta, sida bisfosphonate ugu awoodda badan, zoledronic acid, oo ah qiyaasta 4 mg13 ama 5 mg (qiyaasta ay ansixisay Maamulka Cuntada iyo Dawooyinka). [FDA] ee lafo-jileecu),14 waxay si wax ku ool ah u xakameysaa calaamadaha biochemical ee soo noqoshada lafaha ilaa 1 sano haweenka qaba lafo-guurka postmenopausal. Inkasta oo nolosha nuska bayoolojiga saxda ah ee hadda la isticmaalo bisphosphonates nitrogen-ka kooban ayaa weli ah mawduuca doodda sababtoo ah caqabadaha farsamada ee loo baahan yahay si loo go'aamiyo heerarka bisphosphonate ee kaadida iyo serum, qiyaasaha bisphosphonate alendronate ee xoogga leh waxay soo jeedinayaan nolol nus bayooloji ah oo ka badan 10 sano kadib hal-door IV maamul.15

Muuqaal muhiim ah oo xukuma farmashiyaha kiliinikada ee bifosphonates waa helitaankooda. Fasalka ahaan, bifosphonates waa mid aad u badan. Iyadoo la raacayo, waxay si liidata u nuugaan mareenka caloosha iyo mindhicirka ka dib maamulka afka (guud ahaan nuugista <1% ee qiyaasta afka), halkii ay maraan gaadiidka paracellular sababtoo ah ma aha lipophilic. lagu hayo qalfoofka, halka inta soo hadhay lagu dabar-gooyo kaadida iyada oo aan la dheef-shiidin. Qaadashada qalfoofka iyo sii hayntu waxay ugu horreyn ku xiran tahay arrimaha martida loo yahay (shaqada kelyaha, heerka isbeddelka lafaha, iyo helitaanka goobta xidhitaanka) iyo bisphosphonate awoodda matrixka lafaha guud ahaan xaaladaha caafimaad waxaana la rumeysan yahay in ay ka tarjumayso kala duwanaanshaha lafaha lafaha.16

Caqabada hore ee bukaanno badan ayaa loo qoray daaweynta bisphosphonate afka waa dhib la'aanta la xiriirta maamulka afka maalinlaha ah (u baahan bukaanada inay toosanaadaan 30 daqiiqo oo ay ka fogaadaan inay cunaan cunto kasta 2 saacadood ka hor iyo ugu yaraan 30 daqiiqo ka dib qaadashada kiniinka) iyo tan caadiga ah. xiriirka leh calaamadaha caloosha iyo mindhicirka. Horumarka ugu dambeeyay ee diyaarinta dawooyinka u dhigma ee u oggolaanaya toddobaadkii hal mar (alendronate ama risedronate) ama xitaa bishiiba (ibandronate ama risedronate) maamulka afka ayaa si weyn u saameeyay bixinta bifosphonate ee bukaannada intooda badan kuwaas oo ku habboonaanta (oo sidaas awgeed u hoggaansanaanta daaweynta) ay ahayd arrin iyo ayaa u dhiganta waxay keentay heerar sare oo u hoggaansanaansho.17,18 Dheeraad ah, helitaanka diyaargarowga IV (pamidronate, ibandronate, iyo zoledronic acid), taas oo inta badan xaaladaha bukaan-socodka u baahan yihiin xitaa qiyaas yar oo joogto ah, ayaa meesha ka saartay saameynta xun ee caloosha iyo mindhicirka ee bukaannada qaarkood. lagu maareeyo bifosphonates afka, in kasta oo heerka falcelinta wejiga ba'an ee lagu garto calaamadaha hargabka (xummad-hooseeya, myalgias iyo arthralgias, ama madax-xanuun) ay kordheen bukaanada qaata IV halkii ay ka ahaan lahaayeen daaweynta bisfosphonate afka.14

Doorka Dhaqanka Kiliinikada

Sida kor ku xusan, bisphosphonates waxay kor u qaadaan apoptosis ee osteoclasts si firfircoon uga qaybqaataan hoos u dhaca macdanta dusha lafaha. Sidaa awgeed, bisfosphonates waxay noqdeen daaweynta aasaasiga ah ee lagu maareeyo xaaladaha lafaha oo lagu garto kororka lafaha dhexdhexaadinta osteoclast. Dib-u-soo-celinta xad-dhaafka ah ee noocan oo kale ah waxay hoos timaadaa dhowr xaaladood oo cudur-sidaha kuwaas oo bisphosphonates hadda sida caadiga ah loo isticmaalo, oo ay ku jiraan noocyo badan oo lafo-osteoporosis ah (dhallinyaro, postmenopausal ama involutional [senile], glucocorticoid-induced, transplant-ku-tallaalid, dhaqdhaqaaq-la'aan, iyo androgen-la'aanta la xidhiidha). Cudurka Paget ee lafaha, osteogenesis imperfecta (OI), hypercalcemia, iyo malignancy metastatic ilaa lafaha.

In kasta oo mid kasta oo ka mid ah bisfosphonates-ka nitrogen ka kooban yahay uu ka awood badan yahay bisfosphonates-ka aan nitrojiinka ku jirin, awoodda ay u leeyihiin inay xakameeyaan dhaqdhaqaaqa osteoclast (sida lagu qiyaaso calaamadaha biochemical ee wareegga lafaha) way kala duwan tahay. Si kastaba ha ahaatee, in xakamaynta sare ee leexashada lafaha ay khusayso ka hortagga jabka ayaa weli ah mid la go'aamin doono. Runtii, xogtu waxay soo jeedinaysaa in u hoggaansanaanta daaweynta bisphosphonate ee muddada-dheer, halkii ay ka ahaan lahayd bisfosphonate gaar ah oo loo isticmaalo, waa qodobka ugu muhiimsan ee lagu go'aaminayo waxtarka daaweynta xaddidaadda khatarta jabka. wax ka qabashada welwelka bukaanka ee badbaadada daawada iyo waqtiga, takhaatiirta ayaa si weyn u wanaajin kara u hoggaansanaanta.19,20 Haddii qiyaasta bifosphonate ee afka toddobaadlaha ah ama bilaha ah ay keento heerar sare oo u hoggaansanaanta daaweynta hadda lama garanayo.

osteoporosis

Xaaladda caafimaad ee ugu caansan ee daaweynta bisphosphonate loo isticmaalo waa osteoporosis, xaalad qalfoof ah oo lagu garto xoogga lafaha oo daciifa taasoo keentay khatarta sii kordheysa ee jabka. Sida hore loo xusay, lafo-jileecu waa cudur kiliinikada kala duwan leh oo leh asal kala duwan, oo ay ku jiraan luminta hoormoonka (postmenopausal iyo androgen-deprivation), iatrogenic (glucocorticoid-induced and transplant-related), jireed (ma dhaqaaqi karo), iyo hidde-side (tusaale, dhallinta iyo dhallinta). OI-ku-xiran). Badanaa xaaladahani waxay isku dhacaan bukaanada gaarka ah.

Lafo-jileecu ka dib waxa lagu gartaa dheellitir la'aanta u dhaxaysa osteoclast-dhexdhexaadinta lafaha iyo samaynta lafo-dhexdhexaadinta osteoblast sida dib-u-soocidda lafaha ayaa kordhay. Isku dheelitir la'aantan qaraabadu waxay keenaysaa dhimista cufka lafaha, xumaanshaha microarchitecture lafaha, iyo khatarta jabka oo kordhay. Intii lagu jiray 2-dii sano ee la soo dhaafay, daaweynta bisphosphonate waxay noqotay hormuudka faragelinta kiliinikada ee osteoporosis postmenopausal sababtoo ah awoodda bisphosphonates si ay si xushmad leh u xakameyso dhaqdhaqaaqa osteoclast oo ay dib u dhigto dib u soo noqoshada lafaha. Hoos-u-dhaca jabka iyo korodhka isku-dhafan ee cufnaanta lafaha guud ahaan lagu arko isticmaalka biphosphonate ayaa la rumeysan yahay inay ka dhalanayso hoos u dhaca inta jeer ee firfircoonida unugyada cusub ee dib-u-qaabaynta ee ay sameeyeen osteoclasts, oo leh ilaalin qaraabo ah (ugu yaraan bilowga) dhaqdhaqaaqa osteoblast. Sidan oo kale, xasilinta bilawga ah iyo sii-haynta isku-xirnaanta trabecular waxay u oggolaanaysaa muddada kaydinta macdanta sare ee dhismaha qaabdhismeedka in la dheereeyo, taas oo kordhinaysa boqolkiiba unugyada qaabdhismeedka lafaha oo gaaraya heerka ugu sarreeya ee macdanta.22 Tani waxay kordhinaysaa heerka celceliska celceliska Macdanta lafaha ayaa hoosta ka xariiqaysa labadaba hagaajinta cufnaanta lafaha iyo dhimista khatarta jabka ka dib daaweynta bifosphonate.

Muhiimad ahaan, doorkan bisphosphonates waxaa si aan toos ahayn u dhibay joojinta hore ee estrogen iyo progesterone cududda Hindisaha Caafimaadka Haweenka (WHI), sababtoo ah welwelka ku saabsan heerka korodhka cudurrada halbowlaha wadnaha iyo kansarka naasaha ee haweenka helaya daaweynta hoormoonka. Dhakhaatiirta iyo bukaanada intooda badan, natiijooyinka WHI waxay si wax ku ool ah u xaddideen dhaqanka daaweynta osteoporosis postmenopausal ee daaweynta hoormoonka beddelka, inkastoo caddaynta xooggan ee lagu bixiyay WHI iyo daraasado hore oo ah in estrogen aad waxtar u leh ka hortagga jabka.23

Waxaa ka mid ah bisfosphonates afka ah, labadaba alendronate iyo risedronate labadaba si buuxda ayaa loo muujiyay si loo yareeyo tirada vertebral24�26 iyo jabka sinta, 24,27 horumarka cilladaha vertebral, iyo dhuminta dhererka haweenka postmenopausal ee leh osteoporosis.28 Ibandronate, ayaa dhawaan la helay labadaba diyaargarowga afka iyo IV, ayaa la muujiyay si loo yareeyo khatarta jabka laf dhabarta, 29,30 inkastoo qiyaasaha cabbirka muunada ee la isticmaalay aysan u oggolaanin awood ku filan oo lagu ogaanayo saameynta jabka aan vertebral ama sinta. Khatarta jabka ee qaraabada ah ee dhimista vertebral, sinta, iyo meelaha aan vertebral-ka ahayn ee haweenka menopause post-menopausal ee leh osteoporosis la yaqaan ka dib sanadaha 3 ee daaweynta bifosphonate ayaa la barbardhigay Jadwalka.

Hoos u dhigista dhacdooyinka jabka ayaa dhacaya ka hor inta aan la arki karin isbeddellada muuqda (oo lagu qiyaaso laba-tamar ee raajo absorptiometry [DXA]) ee cufnaanta macdanta lafaha (BMD), taas oo soo jeedinaysa in xasilinta microarchitecture lafaha hadda jira ama lafaha lafaha oo yaraaday waxay ku filan tahay dhimista khatarta jabka.31 Maalin kasta. isticmaalka alendronate ee qiyaasaha 10 mg ilaa 10 sano ayaa si fiican loo dulqaatay oo aan lala xiriirin natiijooyinka qalfoofka xun. Lafo hoose ama lafo-jileecu waxay muujiyeen jawaabo la mid ah daaweynta bisphosphonate.32�33

Tijaabada Dhex-dhexaadinta Jabka Kordhinta Muddada Dheer, haweenka postmenopausal ee leh qoorta femoral ee BMD (laakin lama huraan ah DXA-qeexitaanka lafaha) ayaa lagu daaweeyay alendronate maalin kasta 5 sano ka dibna la kala soocay si ay u helaan alendronate ama placebo 5 sano oo dheeraad ah. Dumarka joojiyey daaweynta alendronate waxay lahaayeen tirokoobyo muhiim ah, inkasta oo kiliinikada yar yar, hoos u dhac ku yimid BMD iyo korodhka la xidhiidha calaamadaha biochemical ee isbeddelka lafaha marka la barbardhigo dumarka sii waday daaweynta.36 Muhiimad ahaan, wax farqi weyn ah lagama helin jabka aan vertebral ama dhammaan jabka kiliinikada; si kastaba ha ahaatee, waxaa jiray wax yar oo sarreeya (iyo tirakoob ahaan) khatarta jabka vertebral ee bukaan-socodka ee kooxda placebo (khatarta buuxda, 2.9%), laakiin tani ma ahayn barta dhamaadka daraasadda aasaasiga ah ama sare. Daraasadaha rasmiga ah ee joojinta alendronate oo leh awood dheeraad ah oo xisaabeed oo loogu talagalay qiimeynta jabka ka dib joojinta sida barta ugu dambeysa ee asaasiga ah ama kuwa kale ee bisphosphonate weli ma aysan xaqiijin in, ugu yaraan bukaannada qaarkood ee qaba osteoporosis postmenopausal, fasaxa daroogada ayaa noqon kara mid macquul ah ka dib muddo daaweynta bisphosphonate. .

Daraasadihii ugu horreeyay ayaa la isticmaalay qiyaasta bifosphonate maalin kasta; Daraasado badan oo dhowaan la sameeyay ayaa diiradda saaraya toddobaadle (alendronate iyo risedronate) ama bishiiba (ibandronate, iyo dhawaanta risedronate37), hababka la rumeysan yahay inay leeyihiin farmacodynamic u dhigma qiyaasta maalinlaha ah ee daroogo kasta. Si kastaba ha ahaatee, dhammaan daraasadaha ilaa taariikhda la isticmaalayo daawaynta bisphosphonate toddobaadle ama bille ah oo afka ah ayaa ku tiirsan calaamadeeyayaasha, sida calaamadaha biochemical ee dib-u-soo-celinta lafaha ama isbeddelka BMD ee lagu qiyaaso DXA, halkii ay ka ahaan lahaayeen natiijooyinka jabka aasaasiga ah, si loo go'aamiyo waxtarka. Taas bedelkeeda, tijaabada lafaha, kaas oo ibandronate afka laga qaato maalin kasta oo kale 12 qiyaasood 3dii biloodba mar, ayaa hoos u dhigtay jabka vertebral ee qiyaasta dhexdhexaadka ah, 30 inkasta oo qiyaasta daawadan aysan ansixin FDA si loogu daaweeyo osteoporosis postmenopausal. Si kastaba ha ahaatee, daawaynta toddobaadlaha ah ama bilaha ah ee joogtada ah ayaa la rumeysan yahay inay bayooloji ahaan u dhiganto ka hortagga jabka waxayna noqotay heerka daryeelka.

Dhawaanahan, labadaba ibandronate iyo zoledronic acid ayaa loo oggolaaday maamulka IV si loo daaweeyo lafo-jileec ka dib. Halka ibandronate loo oggolaaday maamulka saddexdii biloodba mar, zoledronic acid waxaa loo oggolaaday maamul sannadkiiba mar. Inta lagu jiro 3-sano Natiijooyinka Caafimaadka iyo Hoos u dhaca Dhacdooyinka Zoledronic Acid Sannadkii Hal mar (HORIZON) muddada daraasadda, maamulka IV ee sannadlaha ah ee zoledronic acid ayaa horseeday hoos u dhac weyn oo ku yimid vertebral (70% hoos u dhaca), sinta (41% dhimis), iyo nonvertebral (25). % hoos u dhigista) jabka, oo leh koror weyn oo BMD ah oo ku dhaca laf-dhabarka, sinta, iyo qoorta femoral.14 Intaa waxaa dheer, maamulka IV zoledronic acid gudaha 90 maalmood ee dayactirka jabka miskaha qalliinka iyo sannad kasta ka dib ayaa dhawaan la muujiyay si loo yareeyo dhacdooyinka wax kasta. jabka cusub ee kiliinikada ee 35% waxaana lala xiriiriyay 28% dhimista dhimashada .38 Dheeraad ah, bukaanada lagu daaweeyay alendronate toddobaadle ah ugu yaraan 1 sano, u beddelashada zoledronic acid sannadkii ma ahayn mid ka hooseeya sii wadida alendronate, laakiin maamulka sanadka. Waxaa door biday bukaanada.39 Haddii diyaargarowga IV uu noqon doono hababka bisphosphonate ee la door bidayo ee maaraynta osteoporosis postmenopausal ama ka dib jabka sinta lama garanayo. Si kastaba ha ahaatee, way caddahay in bixinta IV bisphosphonate ay si gaar ah faa'iido u leedahay haddii u hoggaansanaanta ama dulqaadka caloosha iyo mindhicirka ay caqabad ku tahay daaweynta afka ama haddii bukaanku door bidaan ku habboonaanta daaweynta IV bisphosphonate.

Ugu dambeyntii, cilmi-baarisyo dhowr ah ayaa diiradda saarey waqtiga ugu fiican ee daaweynta bisphosphonate ee maaraynta lafo-jileecu iyada oo lala kaashanayo wakiilada kale ee dawooyinka ee leh dhaqdhaqaaqa lafaha. Inkasta oo la isku daro bisfosphonate oo leh estrogen ama modulator-ka-soo-dhoweynta estrogen-receptor raloxifene waxay keenaysaa koror yar oo BMD ah marka loo eego daaweynta bisfosphonate oo keliya, ma jirto xog tijaabo caafimaad oo wanaagsan oo ku saabsan heerarka jaban ee taageeraya isticmaalka joogtada ah ee isku-dhafkan.40,41 Daraasado kale Waxay qiimeeyeen bukaanada helaya dherer buuxa oo buuxa 1�84 hormoonka parathyroid aadanaha (PTH) ama jajabka PTH 1�34 (teriparatide) . waxay qabataa daaweyn isku dhafan iyadoo la adeegsanayo bisphosphonate iyo midkood PTH ama teriparatide.42 Saamaynta ugu adag ee lafaha anabolic ayaa lagu arkay bukaanada qaata daaweynta hore ee PTH ka dibna lagu ilaaliyo daaweynta bisphosphonate.44

Glucocorticocorticoid-ku-soo-saaray iyo Lafo-jileec-ku-tallaalidda Lafo-beelka

Halka bifosphonates ay noqdeen doorashada daweynta aasaasiga ah ee daaweynta osteoporosis postmenopausal, qaar yar ayaa aqoonsan in daaweynta glucocorticoid ay keento lafo lumis. Daraasad dhowaan la sameeyay ayaa lagu ogaaday in bukaanada badankood ee qaata daaweynta glucocorticoid ee muddada-dheer aysan helin qiimeyn BMD joogto ah ama warqad dhakhtar u qoraya wax daawo ah oo loogu talagalay maareynta osteoporosis. . Shaqadii dhawaa waxay muujisay in, bukaanada qaata qiyaasta maalinlaha ah ee ugu yaraan 49 mg ee prednisone, alendronate waxay ka hortagtay luminta lafaha si ka waxtar badan marka loo eego fitamiin D7.5 analooga alfacalcidol. leh taariikhda jabka, kuwa qaba rheumatoid arthritis-ka, ama kuwa qaata qiyaaso badan oo glucocorticoid ah, daaweynta bisphosphonate waa kharash-ool ah.3

Sidaa darteed, risedronate ayaa loo oggolaaday gudaha Mareykanka labadaba ka hortagga iyo daaweynta GIO iyo alendronate ee daaweynta GIO. Labaduba waxay aad waxtar u leeyihiin marka qaadashada kalsiyumka iyo qaadashada fitamiin D ay ku filan yihiin. Sidoo kale, daaweynta IV ee mid ka mid ah pamidronate ama ibandronate ayaa lagu muujiyay inay xaddidayso luminta lafaha ee daaweynta glucocorticoid, 52,53 inkastoo midkoodna aan weli loo oggolaan muujintan. Waxaa xusid mudan, cilmi-baarisyo badan ayaa diiwaangeliyay in labadaba daaweynta afka iyo IV-bisphosphonate ay awood u leeyihiin inay xaddidaan luminta lafaha ee inta badan ku dhaca xubin adag54�58 ama dhuuxa lafta beddelka.59�62

Ugu dambeyntii, daraasad dhowaan la sameeyay ayaa muujisay in bukaannada GIO ee lagu daaweeyay teriparatide ay si weyn u kordhiyeen lafdhabarta lumbar BMD iyo jabka cusub ee laf dhabarta marka loo eego bukaanada helay alendronate maalin kasta inta lagu jiro koorsada bilaha 18 Haddii teriparatide ay tahay in lagu beddelo daaweynta bisphosphonate sida daaweynta. doorashada bukaanada qaba lafo-jileeca ee qaata daawaynta glucocorticoid ee muddada-dheer ayaan weli la garanayn.

Lafo-jileeca oo ay keento Dhaq-dhaqaaq-la'aan iyo Sababaha kale ee Luminta Lafaha Ba'an

Bukaannada aan dhaqaaqin, sida kuwa dhawaanta dhaawac ka soo gaaray laf-dhabarta ama dhacdo maskaxeed, ayaa si degdeg ah u lumay lafo, taasoo keenta khatarta sare ee jabka, hypercalcemia, iyo nephrolithiasis joogto ah. Labada afka ah (alendronate) 64 iyo IV (pamidronate) 65 bisphosphonate therapy ayaa lagu muujiyay inay hoos u dhigayaan luminta laftan waxayna yareeyaan calaamadaha biochemical ee dib u soo noqoshada lafaha. Si kastaba ha ahaatee, tirada tijaabooyinka caafimaad ee la sameeyay iyadoo la adeegsanayo labadan dawooyin ayaa weli ah kuwo yar. Sidaa darteed, dhacdooyinka jabka, heerarka nephrolithiasis, iyo badbaadada muddada dheer ayaa weli ah in la go'aamiyo.

Si ka duwan luminta lafaha guud ee dhaca ka dib dhaqdhaqaaq-la'aanta, luminta lafaha xuubka xuubka xuubka xuubka oo leh dabacsanaan la xiriirta maqaar-galaha ayaa ah dhib joogto ah oo ku yimaada bukaanada qaata wadarta sinta arthroplasty. Alendronate66 iyo risedronate67 labaduba waxay hoos u dhigaan laftan ba'an ee xuubka xuubka proximal, inkastoo saameynta muddada dheer ee daaweynta bisphosphonate ee ilaalinta sharafta maqaar-galaha aan wali la soo sheegin.

Cudurka Paget ee Lafaha

Halka postmenopausal osteoporosis lagu garto luminta lafaha guud ee korodhka dhaqdhaqaaqa osteoclast, Cudurka Paget ee lafaha ayaa ku lug leh 1 ama meelo badan oo dib-u-qaabaynta lafaha ah, taas oo dardargelinta laf-dhabarka osteoclast-dhexdhexaadinta laf-dhabarka ay ku xigto laf-dhabarka osteoblast-dhexdhexaadinta lafaha. Lafaha dhuuban ee sida liidata loo samaystay iyo lamellarka waxay inta badan keentaa xanuun, jab, iyo qallooc halis ah, oo ay ku jiraan foorarsiga lafo dhaadheer oo miisaan leh, balaadhinta madaxa, ama qallafsanaan kale oo badan oo lafaha ah. Sida asaasiga ah ee daaweynta cudurka Paget ee lafaha, bisphosphonates waxay si qoto dheer u xakameysaa kororka lafaha ee hoos yimaada cudurka, guud ahaan taas oo keenta caadi ahaan heerarka fosfatase serum alkaline ee loo isticmaalo si loola socdo dhaqdhaqaaqa cudurka. Afka (alendronate68 iyo risedronate69) iyo IV (pamidronate70 iyo zoledronic acid71 dhawaan la ansixiyay) bisphosphonates waa dhammaan FDA-loo oggolaaday daawaynta cudurka Paget ee lafaha waxayna si weyn u beddeleen daawaynta hore ee FDA-ansixisay (non-nitrogen-ka ku jira bisphosphonates) iyo calciton sababtoo ah awoodda ay u leeyihiin inay xakameeyaan dhaqdhaqaaqa osteoclast ayaa ka sarreeya.

Bisphosphonates ee Malignancy

Kansarro badan ayaa ah osteotropic oo ama metastasize ilaa qalfoofka (oo ay ku jiraan laakiin aan ku xaddidnayn malignancies asaasiga ah ee naaska, prostate, sambabada, ama kelyaha) ama ugu horrayn waxay ku koraan dhuuxa lafta (multiple myeloma), halkaasoo koritaankani uu si joogto ah u horseedo hypercalcemia, oo daran. lafo xanuun, burbur lafaha, iyo cudurada pathologic. Runtii, qalfoofku waa goobta ugu badan ee cudurka metastatic, iyo 90% ama ka badan bukaanada qaba kansarka horumaray waxay yeeshaan nabarro lafaha lafaha.73

Kansarka naasaha

Bukaannada qaba kansarka naasaha ee metastatic ilaa lafaha, daawaynta diyaargarowga IV ee pamidronate,74�76 zoledronic acid,77,78 iyo ibandronate79 ayaa lagu muujiyay in ay si weyn u yareeyaan xanuunka lafaha waxayna yareeyaan dhibaatooyinka lafaha. Bifosphonates-ka nitrogen-ka ee afka laga qaato, kaliya ibandronate (oo lagu bixiyo qiyaasta maalinlaha ah ee 50 mg) ayaa wax ku ool u ah dhimista xanuunka lafaha iyo xaddididda dhibaatooyinka lafaha ee kansarka naasaha.80,81

Haddii isticmaalka bisphosphonate uu door isku mid ah ku leeyahay daaweynta haweenka qaba kansarka naasaha, laakiin ma jiraan wax caddayn ah oo ku saabsan metastases lafaha lafaha hadda lama garanayo, laakiin waxaa soo jeedinaya natiijada kicinta ah in haweenka qaba kansarka naasaha ee xaddidan ee naasaha kuwaas oo helay clodronate muddo 2 sano ah ay hoos u dhac weyn ku sameeyeen. horumarinta lafaha lafaha marka la helayo daaweynta biphosphonate, iyo sidoo kale hoos u dhigista guud ahaan dhimashada marka ay la socdaan sanadaha 6 Inkasta oo daaweynta bisphosphonate ee haweenka qaata daaweynta hoormoonka ee kansarka naasaha ay heleen feejignaan yar, doorka muhiimka ah ee xaddidaya isbeddelka lafaha ilaalinta sharafta qalfoofka (gaar ahaan dumarka premenopausal ka mid ah kuwaas oo yaraanta estrogen farmashiyaha lagu soo bandhigay) ayaa dhawaanahan la mahadiyay.82 Istaraatiijiyada maaraynta bisphosphonate ee ugu fiican ee u dhiganta hababka farmashiga ee la heli karo 83 mg IV oo la bixiyo 4dii biloodba mar) 6 ayaa dhawaan la soo bandhigay si looga hortago lafo-beelka haweenka premenopausal ee qaata daaweynta endocrine-ku salaysan ee kansarka naasaha ee hormoonka ah. Sidoo kale, haweenka postmenopausal ee qaba kansarka naasaha ee hormoonka ku-tiirsanaanta hore, toddobaadle ah risedronate afka ayaa dhawaan la muujiyay si looga hortago lafo-beelka kuwa qaata daaweynta aromatase inhibitor.84

Cancer Prostate

Kansarka naasaha waxaa lagu gartaa nabarrada lafaha lafaha, laakiin lafaha lafaha ee kansarka qanjirka 'prostate' ayaa lagu tilmaamay inuu yahay osteoblastic. Doorka kororka lafaha ee kansarka qanjirka 'prostate' ayaa dhawaan la aqoonsaday.86 Ka mid ah bisphosphonates, kaliya zoledronic acid ayaa la muujiyay si loo yareeyo dhacdooyinka lafaha lafaha ee ragga qaba kansarka qanjirka 'prostate' ee hormoonka, 87,88 oo leh khatar buuxda 11% 2 sano marka la barbar dhigo placebo.

Sida dumarka lagu sameeyo ka-baxa hormoonnada kiimikaad, ragga qaba kansarka qanjirka 'prostate' ee ka jawaaba hormoonka kuwaas oo qaata daawaynta androgen-la'aanta waxay ka faa'iideysan karaan isticmaalka bisphosphonate macquul ah. Halka daawaynta IV pamidronate ay ka hortagtay luminta lafaha labadaba sinta iyo laf dhabarta ee ragga qaba kansarka qanjirka 'prostate' ee aan lahayn qanjirka 'prostate' kuwaas oo helay daaweynta gonadotropin-sii daynta hoormoonka agonist, 89 hal dose oo sanadle ah oo IV zoledronic acid ayaa dhawaan la soo bandhigay si ay u keento korodhka laf dhabarta iyo sinta labadaba. BMD (halkii laga heli lahaa hoos u dhaca lagu arkay bukaanada qaatay placebo). Natiijooyinkani waxay muujinayaan in daawaynta IV bisphosphonate ee sanadlaha ah ay noqon karto mid waxtar leh si loo ilaaliyo daacadnimada lafaha ee ragga aan lahayn androgen-ka-dhimanka90 waxayna la mid yihiin natiijooyinka la helay jadwal qiyaaseed oo badan. si looga hortago luminta BMD ee misigta waxaana lala xiriiriyay kororka 91% ee lafaha lumbar.2.5

Meelo badan

Myeloma badan, faafinta clonal ee unugyada balasmaha malignantiga ah ee ku dhex jira godka dhuuxa lafta waxay keenaysaa lafo-beelka iyo burburka lafaha, xisaabinta inta badan cudurrada la xidhiidha cudurka. Daraasado dhowr ah ayaa muujiyay in labadaba pamidronate iyo zoledronic acid ay leeyihiin door muhiim ah oo palliative si loo yareeyo dhacdooyinka hypercalcemia iyo lafaha lafaha lafaha ee la xidhiidha myeloma, 93-95 gelinta IV bisphosphonates ee xarunta daaweynta hadda jirta si looga hortago loona daweeyo myeloma. cudurka lafaha. Waqtigan xaadirka ah, ma jirto wax taageero ah oo ku saabsan daaweynta bisphosphonate ee bukaanada qaba myeloma qiiqa, myeloma oo aan lahayn cudurka lafaha ee la xidhiidha, ama monoclonal gammopathy ee muhiimka ah ee aan la go'aamin, ama daaweynta bisphosphonate afka laguma talinayo maaraynta cudurka lafaha myeloma ee la xidhiidha.

Marka la eego in bukaannada qaba myeloma badan ay leeyihiin dhacdooyinka ugu sarreeya ee ONJ ee dhammaan bukaannada Oncology ee qaata daaweynta bisphosphonate, doorashada bisphosphonate, qiyaasta, iyo muddada daawaynta ayaa diiradda saaraya doodo la taaban karo, oo lagu soo ururiyay tilmaamaha dhaqanka kiliinikada ee Bulshada Maraykanka ee Clinical. Oncology96 iyo, dhawaanahan, bayaan la isku raacsan yahay oo ka yimid Mayo Clinic Myeloma Group97 oo ku salaysan dib u eegis dhamaystiran oo suugaanta kobcaysa. Bayaanka la isku raacsan yahay ee Mayo, faleebo bille ah oo pamidronate ah (sababtoo ah khatarta sare ee ONJ ee bukaannada qaata zoledronic acid) ayaa la door biday, iyadoo la joojinayo 2 sano ka dib haddii bukaanku gaaro cafis oo u baahnayn daaweyn myeloma dheeraad ah. Haddii daaweyn firfircoon weli loo baahan yahay, pamidronate waxaa lagu sii wadi karaa jadwal la dhimay 3dii biloodba mar. Inkasta oo Kooxda Shaqada ee Caalamiga ah ee Myeloma ay guud ahaan ku raacday bayaanka Mayo Consensus, kooxdu waxay soo jeedisay in daaweynta pamidronate la joojin karo ka dib markii bukaanku ku jiro sanadka 1 ee cafiska bukaan-socodka iyo in jadwalka qiyaasta qiyaasta aan la sheegin.98 Sidaa darteed, inkasta oo bisphosphonates ay sii ahaanayaan dhinaca muhiimka ah ee habka farmasiga ee cudurka lafaha myeloma, su'aalaha ku saabsan isticmaalkooda ugu wanaagsan ayaa weli ah.

Cudurada kale

Isticmaalka bisfosphonates ee cudurrada kale ee aan caadiga ahayn ee lafaha, sida kansarka unugyada kelyaha, ayaa lagu muujiyay inuu dib u dhigo bilawga iyo horumarka cudurka lafaha,99 oo soo jeedinaya in bukaanada qaba xaalado caafimaad oo aan caadi ahayn la rumeysan yahay inay saameeyaan qalfoofka sidoo kale waxay ka faa'iideysan karaan bisphosphonate daawaynta Hadda, si kastaba ha ahaatee, xogta xaddidan waxay taageertaa isticmaalka joogtada ah ee daaweynta bifosphonate ee cudurrada kale.

Daaweynta Bisphosphonate ee Carruurta

Inkasta oo bisfosphonates si weyn loogu isticmaalo dadka waaweyn, tobankii sano ee la soo dhaafay waxay noqdeen kuwa ugu muhiimsan ee daaweynta OI, xanuunka lafaha lafaha ee la iska dhaxlo oo lagu garto tirada lafaha oo aad u yaraaday iyo jilicsanaan daran, oo badanaa ka dhasha isbeddellada hiddo-wadaha nooca I kolajka. Nidaam ay soo saartay Glorieux100 ee pamidronate cyclic IV (oo lagu bixiyo wareegyada 3-maalin kasta 2 ilaa 4 biloodba qiyaasta sanadlaha ah ee 9 mg/kg) ayaa si guul leh loo isticmaalay, taasoo horseedaysa kororka 88% dhumucda kortikal, 46% korodhka mugga lafaha trabecular,101 iyo horumar la taaban karo oo ku saabsan heerka shaqada. Dhawaan, cilmi-baarisyo dhowr ah ayaa muujiyay in alendronate-ka afka uu sidoo kale u horseedi karo koror la taaban karo ee BMD wuxuuna xaddidi karaa jabka OI ee saameeya carruurta. Bukaannada qaba OI waxay muujinayaan korodhka korodhka lafaha lafaha taasoo ka dhalatay kororka osteoclast marka loo eego dhaqdhaqaaqa osteoblast, taasoo keentay in guud ahaan luminta lafaha wareegga dib-u-qaabaynta. si kor loogu qaado samaynta lafaha, in kasta oo ay ku jiraan goobta matrix collagen aan caadi ahayn. Runtii, falanqaynta histomorphometric ee shaybaarada biopsy ee crest crest ee bukaanada qaba OI ee helay therapy pamidronate ayaa muujiyay kororka dhumucda kortikal iyo tirada trabeculae laakiin ma kordhin dhumucda trabecular.102

Inkasta oo daawaynta bisfosphonate si fiican loogu aasaasay OI ee carruurta, xogtu waxay ku xaddidan tahay waxtarka iyo khatarta waxyeellada marka bisphosphonates loo isticmaalo carruurta qaba lafo-jileeca labaad ee jirrooyinka joogtada ah (sida cystic fibrosis, rheumatoid arthritis-ka, ama anorexia nervosa) ama kuwa kuwaas oo uu soo gaaray gubasho daran. Dib-u-eegis nidaamsan oo dhowaan lagu sameeyay daaweynta bisphosphonate ee carruurta iyo dhalinyarada qaba lafo-jileeca labaad ayaa soo gabagabeeyey in caddayn aad u yar loo heli karo si loo taageero bisphosphonates sida daaweynta caadiga ah, inkastoo daaweynta muddada 3 sano ama ka yar ay u muuqato mid si fiican loo dulqaatay.107 Daraasad si fiican loo dhisay ayaa loo baahan yahay. in la sameeyo habraacyo cad oo lagu baaro laguna daweeyo dhammaan noocyada lafo-jileecu ee carruurta.108

Ugu dambeyntii, marka la eego muddada dheer ee nolosha nuska ah ee bisphosphonates iyo caddaynta in pamidronate laga heli karo shaybaarka kaadida ilaa 8 sano ka dib maamulka, 109 daryeel ayaa loo dammaanad qaaday marka la tixgelinayo daaweynta bisphosphonate ee dhalinyarada ama gabdhaha yaryar kuwaas oo gaari doona qaan-gaarnimada taranka toban sano gudahood. ee daaweynta. Waqtigan xaadirka ah, kaliya xaddidan, xogta anecdotal ayaa qiimeysay badbaadada muddada dheer ee pamidronate110 ama daaweynta kale ee bifosphonate inta lagu jiro koritaanka uurjiifka.

Bisphosphonates ee ku jira waxqabadka kiliinikada waxaa loo isticmaalaa in lagu daaweeyo lafo-jileecu, cudurka Paget ee lafaha, lafaha lafaha, myeloma badan, iyo arrimaha kale ee caafimaadka ee leh lafaha jilicsan. Inkasta oo biphosphonates lagu taliyay inay noqoto mid ka mid ah daawaynta safka hore ee osteoporosis post-menopausal, daraasadaha cilmi-baarista ayaa horay uga wada hadlay saameynta xun ee fasalkan daroogada / daawada. Waa lama huraan bukaanada inay kala hadlaan xirfadahooda daryeelka caafimaadka wax ku saabsan doorashooyinka daawaynta ee dhaawacyadooda iyo/ama xaaladooda.

Dr. Alex Jimenez DC, CCST Insight

Walaaca Kiliinikada ee La Xiriira Daaweynta Bisphosphonate

Osteonecrosis ee daanka

Dhacdooyinka caafimaad ee suurtagalka ah ee suurtagalka ah ee la xidhiidha isticmaalka bifosphonates, midkoodna ma helin dareen ka weyn ONJ. Sida ay dib u eegtay Woo et al,111 ku dhawaad ​​​​dhammaan kiisaska ONJ (94%) ayaa lagu sifeeyay bukaanada qaata qiyaaso badan oo bifosphonates IV ah (badanaa aashitada zoledronic iyo pamidronate) ee xaaladaha oncologic. Baahinta bukaanada qaba myeloma waxay u dhaxaysaa 7% ilaa 10%, halka ilaa 4% bukaanada qaba kansarka naasaha ay horumariyeen ONJ.111,112 Dhawaan, si kastaba ha ahaatee, jadwal qiyaaseed oo hoos u dhacay bukaanada qaba myeloma, kaas oo IV bisphosphonate la siiyay bil kasta 1 sanadka ka dibna 3dii biloodba mar ka dib, ayaa la muujiyay inay hoos u dhigtay dhacdooyinka ONJ marka la barbar dhigo faleebo bisfosphonate bishiiba.113

Halka dhacdooyinka ONJ lagu qiyaasay 1 ilaa 10 100kii bukaan ee kansarka kansarka, halista ONJ waxay u muuqataa inay aad uga hoosayso bukaanada qaata daawaynta bisfosphonate afka ee lafo-jileecu, iyada oo lagu qiyaasay dhacdooyinka 1 ee 10,000 ilaa 1 ee 100,000 daaweynta bukaanka sano, inkasta oo qiyaastani ay ku salaysan tahay xog aan dhammaystirnayn.114 Qodobbada khatarta ah ee la xidhiidha waxay u muuqdaan inay yihiin nadaafadda afka oo liidata, taariikhda hababka ilkaha ama isticmaalka ilkaha, iyo soo-gaadhista dheer ee qiyaasta bisfosphonate IV ee sarreeya.115,116 Haddii kiimoterabi isku-dhafan ama isticmaalka glucocorticoid ay keento khatarta sii kordheysa ee ONJ lama garanayo.117 Marka la aasaaso, daryeelka ONJ si weyn ayaa loo taageeraa, iyadoo la raaciyo dawooyinka afka laga qaato ee jeermiska dila, antibiyootiga, iyo qallafsanaanta xaddidan ee lama huraanka ah taasoo horseedaysa bogsasho inta badan kiisaska.118 Inkastoo tilmaamaha caddaynta ku salaysan wakhtigan aan la helin loo asaasay mid kasta oo malignant ama bisphosphonate, fiiro gaar ah u leh nadaafadda ilkaha oo ay ku jirto baaritaanka daloolka afka Arrimaha ilkaha ee firfircoon ama la filayo, labadaba ka hor bilowga bisphosphonate iyo inta daawaynta oo dhan, waxay u badan tahay inay noqdaan kuwa ugu muhiimsan.

Inkastoo isticmaalka bifosphonates iyo horumarinta ONJ si ku meel gaar ah loola xiriiriyay, xiriirka sababa lama aqoonsan. Sidaa darteed, inkasta oo suugaanta sayniska ee kobcaysa ee soo korodhay tan iyo xidhiidhka ka dhexeeya daawaynta bisphosphonate iyo ONJ ayaa markii ugu horreysay la soo sheegay 2003,119 su'aalo badan oo aasaasi ah ayaa weli aan laga jawaabin. Talaabada ugu horeysa ee habkan, koox hawleed ay isugu yeertay Bulshada Maraykanka ee Cilmi-baarista Lafaha iyo Macdanta ayaa dhawaan bixisay qeexitaan heersare ah oo ONJ ah sida joogitaanka lafaha qaawan ee gobolka maxillofacial oo aan ku bogsan 8 toddobaad gudahood ka dib aqoonsiga caafimaadka Care professional.114 Marka la eego yaraanta hadda jirta ee macluumaadka ku saabsan dhacdooyinka dhabta ah, arrimaha khatarta ah, iyo habka kiliinikada ee ka hortagga iyo daaweynta labadaba, daraasadaha aasaasiga ah ee asaasiga ah iyo xayawaanka, iyo sidoo kale tijaabooyin caafimaad oo si fiican loo qaabeeyey, ayaa lagama maarmaan u ah labadaba in la ogaado bukaanada korodhay khatarta horumarinta ONJ oo aad si buuxda u fahamto xidhiidhka ka dhexeeya daawaynta bisphosphonate iyo ONJ.

wadne aamba

Marka laga soo tago walaaca ONJ, walaac kale oo ku saabsan daaweynta bifosphonate, kaas oo dhawaan soo ifbaxay, waa fibrillada atrial. In HORIZON Tijaabada Burburka Pivotal, kaas oo bukaanada lagu daaweeyay sanad walba IV zoledronic acid, korodhka tirakoobka ee dhacdooyinka fibrillada halista ah ee atrial (oo lagu qeexay sida dhacdooyinka keentay isbitaal seexinta ama naafanimada ama lagu xukumay inay nafta halis gelinayaan) ayaa la xusay.14 Aetiology-ga cilladda elektiroonigga ah lama yaqaan. Haddii diyaarinta kale ee bisphosphonate ay la xiriirto heerarka korodhka ah ee fibrillada atrial hadda lama garanayo, laakiin falanqaynta hoc ee ugu dambeysay ee xogta laga helay Tijaabooyinka Dhex-galka Jajabka Xudunta u ah dhacdooyinka fibrillation atrial, inkasta oo cilmi-baaris kiis-ku-saleysan oo ballaaran oo dadweynaha ku salaysan aysan muujinin wax caddayn ah khatarta sii kordheysa ee fibrillada atrial ama flutter isticmaalka alendronate. sidoo kale ma dhicin heerka korodhka ah ee fibrillation atrial lagu arkay HORIZON Tijaabada jabka soo noqnoqda, kaas oo bukaanadu ay heleen IV zoledronic acid ka dib jabka sinta. Inta u dhaxaysa dhakhaatiirta iyo bukaanada midkoodna waa curren si toos ah loo maareeyay ama la tixgalinayo bilaabista daawaynta bifosphonate.

Xad-dhaafka Is-beddelka Lafaha

Sababtoo ah bisphosphonates waxay joojisaa dhaqdhaqaaqa osteoclast, waxaa jiray walaac ah in daaweynta bisphosphonate ee dheeraadka ah ay keento lafo barafaysan, oo lagu garto xakamaynta xad-dhaafka ah ee dib-u-qaabaynta lafaha, awoodda daciifka ah ee lagu hagaajinayo microfractures lafaha, iyo korodhka jilicsanaanta lafaha. Inkasta oo heerarka korodhka ah ee microfractures laga helay eeyaha lagu daaweeyay qiyaaso badan oo bisphosphonates,124 natiijadani uma muuqato mid caadi ah oo ka mid ah haweenka postmenopausal ee qaba lafo-jileeca oo lagu daaweeyay daaweynta afka ama IV bisphosphonate, 22,125 inkastoo kiisaska go'doonsan ee lafaha aadka loo xakameynayo iyo jabka la xidhiidha ayaa la soo sheegay.126,127 Si kastaba ha ahaatee, muddada ugu fiicnayd ee daaweynta bisphosphonate ee osteoporosis postmenopausal, iyo ku dhawaad ​​dhammaan xaaladaha kale ee loo isticmaalo bifosphonates, ayaa weli ah mid aan caddayn.

Hypocalcemia

Hypocalcemia ka dib maamulka bisphosphonate inta badan waxay raacdaa faleebo IV waxayna ku dhici kartaa bukaanada qaba heerarka sare ee lafaha dhexdhexaadinta osteoclast (sida bukaanada qaba Paget disease of bone128 ama buro lafaha lafaha129), hore looma aqoonsan hypoparathyroidism, 130 shaqada kelyaha liidato. , ama hypovitaminosis D daawaynta kahor.

Jawaabta Bararka Ba'an

Qiyaastii 10% ilaa 30% bukaanada hela faleebo bisfosphonate-ka ugu horreeya ee nitrogen-ka ku jira waxay la kulmi doonaan falcelin weji ah oo ba'an, oo inta badan lagu garto pyrexia ku meel gaadh ah oo leh myalgias, arthralgias, madax-xanuun, iyo calaamado hargab u eg. Heerkani wuxuu hoos u dhacayaa in ka badan kala badh faleebo kasta oo xiga, sida heerka 2.8% ayaa la helay ka dib faleebo saddexaad ee tijaabada HORIZON.14 Jawaabta wejiga degdega ah ayaa la aaminsan yahay inay tahay natiijada wax soo saarka cytokine proinflammatory by dhiiga durugsan ?? Unugyada T-yada Mararka qaarkood corticosteroids ayaa faa'iido leh.

Saamaynta xun ee dhifka ah ee daaweynta bisphosphonate ee takhaatiirta ay tahay inay ogaadaan waa caabuq indhaha (conjunctivitis, uveitis, episcleritis, iyo scleritis). Dhibaatadan ayaa la ogaaday inay ku dhacdo daaweynta afka iyo IV-da ee bifosphonate. Daraasadda ugu weyn ee dib-u-eegista ilaa taariikhda, dhacdooyinka qiyaastii 0.1% ayaa laga helay bukaanada lagu daaweeyay risedronate.

Xanuunka Murqaha oo Daran

Inkasta oo dhammaan diyaargarowga afka iyo IV bisphosphonate ay ku qoraan xanuunka murqaha sida saameynta xun ee suurtagalka ah ee macluumaadka qorista, US FDA ayaa dhawaan soo saartay digniin muujinaysa suurtogalnimada xanuunka murqaha ee daran, oo aan awood u lahayn inuu ku dhaco meel kasta ka dib bilawga daaweynta bisphosphonate.134 Tani Xanuunka murqaha ee daran ayaa ka duwanaa jawaab-celinta wejiga ba'an ee hore loo sheegay. In ka yar 120 xaaladood ayaa la soo sheegay dabayaaqadii 2002 ee alendronate iyo badhtamihii 2003 ee risedronate guud ahaan.

Dhibaatooyinka kale ee suurtagalka ah ee daaweynta Bisphosphonate

Dhibaatooyinka kale ee la xidhiidha isticmaalka afka iyo daaweynta bifosphonate IV si fiican ayaa loo aqoonsaday. Cuncunka hunguriga iyo nabaad guurka ayaa ku dhici kara daawaynta bisfosphonate afka, gaar ahaan bukaanada qaba cudurka gastroesophageal reflux ee la yaqaan ama adkaanta hunguriga. Dayactirka adag ee booska toosan ee 30 ilaa 60 daqiiqo ka dib marka la nuugo koob buuxa oo biyo ah, taas oo ku xidhan bifosphonate afka, iyo isticmaalka toddobaadlaha ah halkii diyaarinta maalinlaha ah labaduba waxay u badan tahay inay xaddidaan khatarta waxyeellada xun. Bukaannada aan u dulqaadan karin bifosphonates afka, diyaargarowga IV (sida hore loo xusay) hadda waa FDA la ansixiyay oo aan la xiriirin xanaaqa gastroesophageal.

Qiyaasaha Bisphosphonate iyo heerka faleebo waa in lagu hagaajiyaa bukaanada qaba kelyo-yaraanta dhexdhexaadka ah ama daran. Haddii loo isticmaalo bukaanada leh qiyamka nadiifinta creatine ee ka hooseeya 30 mL/min, bisphosphonates waa in si taxadar leh loo isticmaalo. Gaar ahaan bukaanada qaata diyaargarowga IV, bisphosphonates waxay u horseedi kartaa inay si degdeg ah u xumaato shaqada kelyaha, 136,137 waxay u badan tahay sababtoo ah ururinta maxalliga ah ee kelyaha. Bukaanka qaba kelyo-yaraanta ee hela daaweynta IV bisphosphonate, shaqada kelyaha ka hor iyo ka dib maamulka daroogada waa in la go'aamiyaa. Bukaannada qaba kelyaha khafiifka ah iyo kuwa dhexdhexaadka ah ee daciifka ah, bifosphonates afka ayaa dhif u ah inay sii xumaadaan shaqada kelyaha, waxay u badan tahay sababtoo ah nuuggooda liidata ee guud ahaan mareenka caloosha iyo mindhicirka oo sidaas awgeed xaddidan bioavailability-gaaban.

Su'aalo Aan La Xalin

Bisphosphonates waa la sii waday in loo isticmaalo xaalado kale iyada oo aan la helin tilmaame FDA-ansixisay ee daaweynta. Sida la xusay, kuwan waxaa ka mid ah dadyow kala duwan oo carruurta ah oo leh cufnaanta lafaha, jabka shilalka, iyo dhaqdhaqaaq la'aan daba dheeraatay. Dumar badan oo caafimaad qaba premenopausal oo leh mid ka mid ah osteopenia radiographic ama osteoporosis oo aan lahayn jab iyo dumarka postmenopausal ee qaba osteopenia laakiin aan jabin hadda waxay helayaan daaweynta bisphosphonate. Ilaa inta daraasado dheeraad ah ay ka hadlayaan su'aalahan muhiimka ah ee kiliinikada, waxaa muhiim ah in loo sheego bukaankan oo kale in aan hadda la'nahay xog ku filan oo laga helo tijaabooyinka caafimaad ee si wanaagsan loo xakameeyay si loo go'aamiyo faa'iidooyinka ama khatarta loo qaadan karo waxqabadyadan dawooyinka.

Doorka Calcium iyo Vitamin D

Inkasta oo ay jiraan ujeedooyinka wanaagsan ee dhakhaatiir badan si ay u xaddidaan jabka bukaankooda iyaga oo abuuraya daaweynta bifosphonate, muhiimada hubinta fitamiin D ku filan iyo qaadashada kalsiyum labadaba ka hor iyo ka dib bilawga daaweynta bisfosfat waa inta badan la iska indhatiro. Hypovitaminosis D waxay ku badan tahay dad badan oo bukaan ah kuwaas oo sidoo kale loo qoro daawaynta bifosphonate waxayna si gaar ah ugu badan tahay bukaanada waayeelka ah ee inta badan leh soo-gaadhista qorraxda xaddidan, qaadashada cuntada oo yaraatay, ama qaar ka mid ah naafonimada kelyaha. Fiitamiin D-yaridaan ama yaraanta ayaa xaddidaysa nuugista cuntada ee kalsiyumka, taasoo horseedaysa hyperparathyroidism-ka labaad iyo luminta kaalshiyamka lafaha si loo ilaaliyo normocalcemia. Sidaa awgeed, haweenka da'da ah ee qaba lafo-jileecu, joogteynta hyperparathyroidism-ka labaad ayaa hoos u dhigtay kororka BMD ee laf-dhabarka lumbar si looga jawaabo alendronate toddobaadle ah.138 Inkasta oo xogta hadda la hayo ay bixiso wax fikrad ah oo ku saabsan heerarka serum ee ugu fiican ee 25-hydroxyvitamin D, heerka 30. ng/mL (75 nmol/L) ama ka badan ayaa guud ahaan loo arkaa inay ku filan yihiin; maandooriyaha fitamiin D wuxuu dhacaa kaliya marka heerarku ka sarreeyo 150 ng/mL (374 nmol/L) dib u eegis aad u wanaagsan oo uu dhawaan sameeyay Holick.139

In kasta oo tilmaamaha ilaalinta heerka ugu wanaagsan ee fitamiin D-ga ay si weyn isu beddeleen, annaga oo qaddarinayna in ku filnaan la'aanta fitamiin D-yarida iyo yaraanta ay saamayso qayb aad uga weyn tirada dadka marka loo eego markii hore la aqoonsan yahay, talooyinka qaadashada kalsiyumka ugu fiican ayaa wax yar laga beddelay tan iyo markii uu ka hadlay khabiir. Guddi ay isugu yimaaddeen Machadyada Caafimaadka Qaranka ee 1994.140 Guddigu wuxuu soo gabagabeeyey in qaadashada kaalshiyamka ugu wanaagsan lagu qiyaasay inay tahay 1000 mg / d labadaba haweenka ka horreeya menopausal iyo postmenopausal ee qaata daaweynta beddelka estrogen iyo 1500 mg / d haweenka postmenopausal aan helin estrogen. Ragga da'doodu ka yar tahay 65 sano ayaa lagu qiyaasay inay u baahan yihiin 1000 mg / d oo calcium ah iyo ragga da'doodu ka weyn tahay 65 sano si ay ugu baahan yihiin 1500 mg / d.140 Talooyinka dhowaan ka soo baxay National Osteoporosis Foundation ayaa soo jeediyay qaadashada calcium ee 1000 mg / d labadaba ragga. iyo dumarka da'doodu ka yar tahay 50 sano, oo korodhay ilaa 1200 mg/d laga bilaabo da'da 50 sano ka hor.141 Talooyinkani waxay la socdaan kuwa Guddiga Cuntada iyo Nafaqada ee Machadka Daawada.142 Talooyin dheeraad ah oo ku saabsan qaadashada calcium ee carruurta ayaa faahfaahsan. ee labada machadyada caafimaadka qaranka iyo tilmaamaha machadka caafimaadka.140,142

Ugu Dambeyn

Tan iyo markii ay soo bandhigeen dhaqanka kiliinikada, bisphosphonates waxay beddeleen daryeelka bukaan-socodka ee noocyo kala duwan oo qalfoofka lafaha ah oo lagu garto dib-u-soo-celinta lafaha-osteoclast-dhexdhexaadinta xad-dhaafka ah. Sidaa darteed, isticmaalka macluumaadka iyo garsoorka ee biphosphonates waxay siinaya faa'iido caafimaad oo cad oo loogu talagalay bukaannada si taxadar leh loo doortay oo ka miisaan culus khatarta la xiriirta isticmaalka biphosphonate. Joogteynta qaadashada kalsiyum ku filan iyo fitamiin D-ga ayaa muhiim u ah dhammaan bukaannada qaata daawaynta bifosphonate.

Mahadnaq

Waxaan uga mahadcelineynaa James M. Peterson caawinta tirooyinka.

Diyaarinta maqaalkan waxaa taageeray Abaalmarinta Horumarinta Xirfadda Mayo ee Dr Drake.

Dr Khosla wuxuu taageero cilmi baaris ka helay Procter & Gamble wuxuuna ka soo shaqeeyay guddiga la-talinta ee Novartis.

Erey

• ATP - adenosine triphosphate
• BMD - cufnaanta macdanta lafaha
• DXA – nuugista x-ray-ga tamarta laba-tamar ah
• FDA - Maamulka Cuntada iyo Dawooyinka
• GIO - osteoporosis oo ay keento glucocorticoid
• HORIZON - Natiijooyinka caafimaadka iyo hoos u dhaca dhacdooyinka Zoledronic Acid sanadkiiba hal mar
• IV - xididada
• OI - osteogenesis imperfecta
• ONJ - osteonecrosis ee daanka
• PPi - pyrophosphate inorganic
• PTH - hormoonka parathyroid
• WHI - Hindisaha Caafimaadka Haweenka

Qoraalada

Dib-u-daabacaadda shaqsiyeed ee maqaalkan lama heli karo.

Marka loo eego maqaalka kore, in kasta oo ka faa'iidaysiga bisphosphonates ee dhaqanka kiliinikada ay siiso xirfadlayaasha daryeelka caafimaadka ikhtiyaaro daaweyn cusub oo loogu talagalay cudurrada lafaha, daraasado cilmi baaris oo dheeraad ah ayaa weli loo baahan yahay. Macluumaadka laga soo xigtay Xarunta Qaranka ee Macluumaadka Bayolojiyada (NCBI) Si aad ugala hadasho mawduuca, fadlan xor u noqo inaad waydiiso Dr. Jimenez ama nagala soo xidhiidh at�915-850-0900 .

Waxaa soo saaray Dr. Alex Jimenez

 

Mawduucyo Dheeraad ah: Xanuun Dhabar Ba'an

Xanuunka dhabarka�waa mid ka mid ah sababaha ugu badan ee naafada iyo maalmaha shaqada ka baaqda ee adduunka oo dhan. Xanuunka dhabarku waa sababta labaad ee ugu badan ee booqashooyinka xafiiska dhakhtarka, oo ay ka badan yihiin kaliya caabuqyada neef-mareenka sare. Qiyaastii 80 boqolkiiba dadku waxay la kulmi doonaan xanuunka dhabarka ugu yaraan hal mar noloshooda oo dhan. Laf-dhabarta waa qaab dhismeed kakan oo ka kooban lafo, kala-goysyo, seedaha, iyo murqaha, iyo unugyo kale oo jilicsan. Taas awgeed, dhaawacyada iyo/ama xaaladaha sii xumeeyay, sida�maqaarka herniated, ugu dambeyntii waxay keeni kartaa calaamadaha xanuunka dhabarka. Dhaawacyada isboortiga ama dhaawacyada shilalka baabuurta ayaa inta badan ah sababta ugu badan ee xanuunka dhabarka, si kastaba ha ahaatee, mararka qaarkood dhaqdhaqaaqa ugu fudud ayaa keeni kara natiijooyin xanuun leh. Nasiib wanaag, xulashooyinka daaweynta kale, sida daryeelka xanuunka loo yaqaan 'chiropractic care', ayaa kaa caawin kara yareynta xanuunka dhabarka iyada oo loo marayo isticmaalka isbeddelka laf-dhabarka iyo manfacyada gacanta, ugu dambeyntii hagaajinta xanuunka.

 

MAWDUUC DHEERAAD AH OO MUHIIM AH: Daaweynta miskaha ee lafdhabarta