17032012

Pleno PakaPc3Blok DMS

Dept.Farmakologi & Therapeutik Fak.Ke okteran !S! Me an

Bone
Bone composition 70% mineral (Ca2+ and PO4- as hydroxyapatitie) 22% protein (9 % !ype " colla#en + % proteo#lycans and other materials) $% %ater !%o ma&or types o' (one Compact (cortical) i*e*) lon# (ones) +echanical and protecti,e '-nctions Cancello-s (spon#y) i*e*) ,erte(rae) +eta(olic re#-lation o' calci-m .o-r types o' cells Osteo(lasts Osteoclasts Osteocytes Bone linin# cells

Osteoporosis
/e'ined as red-ction in (one mass and micro-architect-re that leads to s-scepti(ility to 'ract-re

0ormal

Osteoporotic

"ss-e o' Pea1 Bone +ass

Bone mass pea1s in the 202s) starts droppin# in the late 302s and accelerates si#ni'icantly a'ter menopa-se 4is1 'or osteoporosis depends on pea1 mass and rate o' loss Pea1 (one mass depends on
5enetics Calci-m) diet) exercise) etc* in yo-th

T"o #omponent$ o% the Bone

#ortical Bone Den$e an compact &un$ the length o% the long 'one$( %orming a hollo" c)lin er Tra'ecular 'one *a$ a light( hone)com' $tructure Tra'eculae are arrange in the irection$ o% ten$ion an compre$$ion +ccur$ in the hea $ o% the long 'one$ ,l$o make$ up mo$t o% the 'one in the -erte'rae

+$teon$
Principal organi.ing %eature o% compact 'one *a-er$ian canal / place %or the ner-e 'loo an l)mphatic -e$$el$ 0amellae / collagen epo$ition pattern 0acunae / hole$ %or o$teoc)te$ #analiculi / place o% communication 'et"een o$teoc)te$

Bone #ell$
+$teoc)te$ 1 eri-e %rom o$teoprogenitor cell$ +$teo'la$t$ +$teocla$t$

+$teoc)te$2
Trappe o$teo'la$t$ 3n lacunae Keep 'one matri4 in goo con ition an can relea$e calcium ion$ %rom 'one matri4 "hen calcium eman $ increa$e +$teoc)tic o$teol)$i$

+$teo'la$t$
Make collagen ,cti-ate nucleation o% h) ro4)apatite cr)$talli.ation onto the collagen matri4( %orming ne" 'one ,$ the) 'ecome en-elope ') the collagenou$ matri4 the) pro uce( the) tran$%orm into o$teoc)te$ Stimulate o$teocla$t re$orpti-e acti-it)

+$teocla$t$
&e$or' 'one matri4 %rom $ite$ "here it i$ eteriorating or not nee e Dige$t 'one matri4 component$ Focal ecalci%ication an e4tracellular ige$tion ') aci h) rola$e$ an uptake o% ige$te material Di$appear a%ter re$orption ,$$i$t "ith mineral homeo$ta$i$

Mineral
, calcium pho$phate5car'onate compoun re$em'ling the mineral h) ro4)apatite #a106P+7896+*82 *) ro4)apatite cr)$tal$ #ontain Mg( :a( K

Minerali.ation o% the Bone

#alci%ication occur$ ') e4tracellular epo$ition o% h) ro4)apatite cr)$tal$ Trapping o% calcium an pho$phate ion$ in concentration$ that "oul initiate epo$ition o% calcium pho$phate in the $oli pha$e( %ollo"e ') it$ con-er$ion to cr)$talline h) ro4)apatite Mechani$m$ e4i$t to 'oth initiate an inhi'it calci%ication

Bone &emo eling Proce$$

Procee $ in c)cle$ / %ir$t re$orption than 'one %ormation The calcium content o% 'one turn$ o-er "ith a hal%1li%e o% 11; )ear$

Bone &emo eling Proce$$

*ormonal 3n%luence
<itamin D Parath)roi *ormone #alcitonin =$trogen ,n rogen

<itamin D
+$teo'la$t ha-e receptor$ %or 61(2;1 6+*821D8 3ncrea$e$ acti-it) o% 'oth o$teo'la$t$ an o$teocla$t$ 3ncrea$e$ o$teoc)tic o$teol)$i$ 6remo eling8 3ncrea$e$ minerali.ation through increa$e inte$tinal calcium a'$orption Fee 'ack action o% 61(2;16+*821D8 repre$$e$ gene %or PT* $)nthe$i$

UV

7- dehydrocholesterol Vit D3 (cholecalciferol)

"#in

Vit D3 Exogen. Decreased 'O(. Exogen. )alcifediol

Vit D3 25 (OH)D3 (calcifediol) $i%er

* *

25 (OH) D3)

&idney

*
!25(OH2)D3(calcitriol)

,lood )a**

* 'arathyroid

,iological actions

)alcitriol in +lood

,ntire$orpti-e Therap)
+ost 'orms o' osteoporosis are a conse6-ence o' (one loss d-e to an im(alance in (one remodelin# s-ch that (one resorption exceeds (one 'ormation* By decreasin# the n-m(er) acti,ity) and li'e span o' osteoclasts) se,eral therape-tic a#ents s-ppress (one resorption and) indirectly) (one 'ormation* !hese antiresorpti,e a#ents are capa(le o' preser,in# (one mass) sta(ili7in# (one str-ct-re and 6-ality) and red-cin# 'ract-re rates*

Parath)roi *ormone
,ccelerate$ remo-al o% calcium %rom 'one to increa$e #a le-el$ in 'loo PT* receptor$ pre$ent on 'oth o$teo'la$t$ an o$teocla$t$ +$teo'la$t$ re$pon to PT* ') #hange o% $hape an c)to$keletal arrangement 3nhi'ition o% collagen $)nthe$i$ Stimulation o% 3019( macrophage colon)1 $timulating %actor $ecretion #hronic $timulation o% the PT* cau$e$ h)pocalcemia an lea $ to re$orpti-e e%%ect$

Parath)roi *ormone
PT* act$ irectl) to increa$e renal tu'ular calcium rea'$orption an in irectl) to enhance inte$tinal calcium a'$orption -ia it$ $timulator) action on renal 11> cholecalci%erol h) ro4)la$e 6there') increa$ing circulating calcitriol8. The normal ph)$iological role o% PT* on $keletal homeo$ta$i$( "hen $ecrete en ogenou$l)( i$ more comple4 'ut pro'a'l) $er-e$ to regulate 'one remo eling rather than o-erall $keletal ma$$. P!8 exhi(its potent ana(olic e''ects on the s1eleton %hen #i,en exo#eno-sly (y intermittent in&ection the o(ser,ation that architect-ral impro,ements do occ-r %ithin the s1eleton a'ter daily P!8 in&ections

Parathyroid hormone
Intermittent injection stimulate new bone formation CONTRAST to continuous infusion Teri aratide ! rhPT"#$%&'( ) was a ro*ed by +S%,-A for R. of osteo orosis Transient dose%related hy ercalcemia /on0 term effects are not 1nown

#alcitonin
# cell$ o% th)roi glan $ecrete calcitonin Straight chain pepti e 1 32 aa S)nthe$i.e %rom a large preprohormone &i$e in pla$ma calcium i$ ma?or $timulu$ o% calcitonin $ecretion Pla$ma concentration i$ 10120 pg5ml an hal% li%e i$ ; min

Calcitonin
Pe tide from Thyroid C cell -irect inhibition of osteoclast acti*ity /ess effecti*e in cortical bone Salmon calcitonin nasal s ray -ose 233 I+4day calcitonin has inherent anal#esic properties) and may (e -se'-l in the early post 'ract-re period9

#alcitonin
Mechani$m o% ,ction2 - calcitonin i$ potent inhi'itor o% o$teocla$tic 'one re$orption@ 1 in 'one( ma?or action i$ inhi'ition o% o$teocla$tic 'one re$orption@ 1 calcitonin inhi'it$ 'one re$orption an $lo"$ o"n rate o% 'one lo$$@ 1 o$teocla$t$ e$cape %rom the inhi'itor) e%%ect$ o% calcitonin %ollo"ing

+ther S)$temic *ormone$

=$trogen$ 3ncrea$e 'one remo eling ,n rogen$ 3ncrea$e 'one %ormation Aro"th hormone 3ncrea$e$ 'one remo eling Alucocorticoi $ 3nhi'it 'one %ormation Th)roi hormone$ 3ncrea$e 'one re$orption 3ncrea$e 'one %ormation

0ocal &egulator$ o% Bone &emo eling

#)tokine$ 3019 3011 Pro$taglan in$ Aro"th %actor$ 3AF13 TAF1B

A*ailable treatment
Calcium and *itamin "ormone re lacement thera y Selecti*e estro0en rece tor modulators ! S5R6s ) 7is hos honates Calcitonin Parathyroid hormone Other treatments Non% harmacolo0ic inter*ention

Calcium
$88' consensus on o timum calcium inta1e
Daily calcium intake Adolescents Adult up to 65 years Postmenopausal women Elderly 1200-1500 mg 1000 mg 1500 mg

Calcium re arations
Calcium citrate Calcium lactate Calcium 0luconate Calcium carbonate Calcium carbonate < ; mc0 =it -2 5lemental calcium 93m04&33m0 :3m04933m0 '3m04;33m0 '33m040 2;3m04tablet

=itamin 5ssential for intestinal absor tion of calcium -aily recommendation '33 % :33 I+4day 5s > /ow sunli0ht e. osure? elderly? low *itamin - inta1e @ -ecreased ris1 of fracture in healthy elderly with normal inta1e A 76-

*ormone &eplacement Therap) 6*&T8

=$trogen &eplacement Therap)
Mekani$me ker?a2 C e$trogen mengurangi re$or'$i tulang g cara2 1menekan tran$krip$i $itokin $pt 3019 )ang mengin uk$i proli%era$i( i%%eren$ia$i an akti%a$i o$teokla$t. 1?uga mempercepat apopto$i$ o$teocla$t. C li%e$pan ari o$teo'la$t an o$teoc)te$ i 6Estrogen iperpan?ang8 tidak meningkatkan bone formation

---- estrogen is more effective at preventing than restoring.

=%%ek $amping e$trogen2

Sering men?a i ma$alah($ehingga pa$ien ?a i C reinitiation o% uterine 'lee ing C 'rea$t pain('rea$t ten erne$$ =$trogen al$o increa$e$@ C -enou$ throm'oem'oli$m C long1term ri$k o% 'rea$t cancer rop1out.

National Institute of Health ( 2002):mendapati bahwa dengan HRT,terjadi: pening!atan risi!o : "pen#a!it !ardio$as!uler " dan !an!er pa#udara lebih berbaha#a dibanding efe! anti osteoporosis n#a

*ormone$ % cont&
,$ o% recent D*3 $tu )( e$trogen1proge$terone therap) no longer %ir$t1line approach %or

o$teoporo$i$ treatment in po$tmenopau$al "omen ue to increa$e ri$k o% 'rea$t cancer( $troke( <T=$( an po$$i'l) #,D.

3n ication$2
per$i$tent menopau$al $)mptom$( ina'ilit) to tolerate other option$( %ailure to re$pon to other option$.

No

.is# of osteo/orosis 0 4es

)ontraindications to H.2 5
1o 'es

1o H.2 .eassess3 4ear

6ncreassed ris# of ,reast cancer 5

No 'es

)onsider +is/hos. .aloxifene! etc. .eassess yearly

)oronary heart disease /resent 5

No

)onsider +is/hos. .aloxifene! etc. .eassess yearly

'es

H.2 or alternati%e 7//roaches8 reassess yearly

)onsider +is/hos. .aloxifene! etc. .eassess yearly

So( in ca$e *&T i$ to 'e gi-en2

,$k an e4plain care%ull)2 C no contrain ication C i% necce$ar)@ letter o% con$ent C per%orm PapF$ $mear 'e%ore an routinel) a%ter"ar C o mammograph) routinel)

S=0=#T3<= =ST&+A=: &=#=PT+& M+D!0,T+&S 6S=&M$8

Merupakan kelompok o'at )ang2 C mengikat re$eptor e$trogen C 'er$i%at ti$$ue1$electi-eCCCC #ontoh2 1ralo4i%ene111 1 e$trogen agoni$t in 'one 1 e$trogen antagoni$t in 'rea$t 1 inacti-e in en ometrium
Note: Estrogen Receptor (ER): $> ESR1---ER , found in uterus,vagina,ovaries, - mammary glands,vascular 2 ESR2---- ER!, found in prostate,"one,lung,"rain - vascular

S=0=#T3<= =ST&+A=: &=#=PT+& M+D!0,T+&S 6S=&M$8

&alo4i%ene2 3ncrea$e BMD in -erte'ral an non1 -erte'ral@ C -erte'ral %racture ri$k ecrea$e C non1-erte'ral %racture ri$k GG

Ho9e%er8 li#e estrogen!raloxifene increase the ris# of %eno:s thro;+oe;+olis; 're/aration8 E%ista< =o ;g!once daily./ 5>>3+:lan

C lo"er$ 0D0 chole$terol

Parath)roi *ormone 6PT*8

C Principal regulator o% calcium homeo$ta$i$ C Stimulate$ 'one %ormation C !$e alone or in com'ination "ith antire$orpti-e agent$ C Potent e%%ect on %racture$2 re uction o% 9; 1 9HI in -erte'ral %racture$ an 3; 1 7;I in non-erte'ral %racture$ 1

7is hos honates

7enefit Potent inhibitor of bone resor tion Reduce osteoclast recruitmentAacti*ity Safe 6ost effecti*e R.BB Ris1 /ow oral bioa*ailability !$%&C) ,ood? calcium? iron? coffee? tea? oran0e juice decreased absor tion DI discomfort Rarely % eso ha0itis "i0h cost

Bisphosphonates
!he antiresorpti,e e''ects appear to res-lt 'rom their inhi(ition o' the en7yme 'arnesyl pyrophosphate synthase (.PP:) in osteoclasts* .PP: is a 1ey en7yme in the me,alonate path%ay) %hich #enerates isoprenoid lipids -tili7ed 'or the post-translational modi'ication o' small 5!P-(indin# proteins that are essential 'or osteoclast '-nction* !he inhi(ition o' protein prenylation and the disr-ption o' the '-nction o' these 1ey re#-latory proteins explains the loss o' osteoclast acti,ity*

Other treatment
,luoride =itamin E2 Strontium ranelate 6eunier PF> The effect of strontium ranelate on the ris1 of *ertebral fracture in women with ostmeno ausal osteo orosis> N5F6 233'G&;3H';8%9: Statins

5.erciseAOsteo orosis
5.ercise effect
Adolescent % Increased ea1 bone mass 5lderly % Small increase in 76,itness may re*ent fallin0 @

5*idence%based data
Reduction of hi Ale0 fractures in obser*ational studies

;''ects o' ;xercise on Bone

!%o types o' st-dies cond-cted Compare trained athletes %ith sedentary people <thletes and chronic exercisers ha,e hi#her B+/ Competiti,e r-nners in =0s ha,e >40% #reater B+/ than controls ?ei#ht li'ters ha,e @0-3 % #reater spine B+/ !ennis players ha,e 30% #reater thic1ness o' dominant h-mero-s Correlate le,el o' 'itness %ith B+/ (;''ect not o(,io-s) ;arly li'e experience is important (Pea1 B+/) ?omen %ho #et hip 'ract-res ha,e lo%er le,els o' occ-pational or leis-re acti,ity 'rom @ -4 years old :i#ni'icant associations (et%een hip B+/ and early-

Consult your doctor first

Other measures
Treat redis osin0 factors ,all re*ention
Correct *isual im airment A*oid dru0s % 7Is? hy notics? antide ressant? dru0s cause hy otension 5.trinsic factors

5.ternal hi

rotector

-ecrease the ris1 of hi fracture by ;3C in 2 small studies

Thank Jou.