OSTEOPOROSIS
I n v i t e d P a p e rN. Sema Akalm
M.D. S u b -d e p a rtm e n t o f E n d o c rin o lo g y , D e p a rtm e n t o f In te rn a l M e d ic in e , S c h o o l o f M e d ic in e , M a rm a ra U n iv e rs ity , Is ta n b u l Turkey.ABSTRACT
O s te o p o ro s is re p re s e n ts th e m o s t c o m m o n form of m e ta b o lic b o n e d is e a s e . Its e p id e m io lo g y , p a th o g e n e s is , c lin ic a l m a n ife s ta tio n s , ra d io g ra p h ic an d la b o ra to ry fe a tu re s , b o n e d e n s ity m e a s u re m e n ts , an d tre a tm e n t a re d is c u s s e d .K ey W ords
: P o s tm e n o p a u s a l o ste o p o ro s is , B o n e m in e ra l d e n s ity , H R T, B is p h o s p h o n a te sIN TR O D UCTIO N
O s te o p o ro s is is th e m o s t c o m m o n ly e n c o u n te re d bone d is e a s e . It is a m a jo r risk fa c to r fo r fra c tu re an d leads to c o n s id e ra b le m o rb id ity , m o rta lity and e xp e n se . T his s k e le ta l d is o rd e r is c h a ra c te riz e d by tw o e le m e n ts th a t d is tin g u is h it fro m o th e r c a u s e s o f o s te o p e n ia such as o s te o m a la c ia an d h y p e rp a ra th y ro id is m : low bone m a s s an d m ic ro a rc h ite c tu ra l d is ru p tio n .L o w b o n e m a s s is a c h a ra c te ris tic fin d in g in o s te o p o ro s is . T h e b o n e th a t is p re s e n t is n o rm a lly m in e ra liz e d , w h ic h d is tin g u is h e s o s te o p o ro s is from o s te o m a la c ia (1 ).T h e re is d is ru p tio n of th e norm al a r c h ite c tu r e .F e w e r b o n y s p ic u le s a re s e e n in o s te o p o ro tic b o n e and th e y are th in n e r th a n norm al ; in a d d itio n ,th e re a re h o riz o n ta l “s tru ts ” th a t do n o t jo in up to a n y o th e r s tr u c tu re , a n d th e r e b y p ro v id e no s tru c tu ra l s u p p o rt. T h is m ic ro a rc h ite c tu ra l d is ru p tio n le a d s to s k e le ta l fra g ility (2,3). T h is s tr ic t d e fin itio n , o f o s te o p o r o s is is la rg e ly h is to lo g ic . In p ra c tic e , o n e d e a ls m a in ly w ith d e c re a s e d b o n e d e n s ity , o r o s te o p e n ia , w ith o u t e x a m in in g b o n e h is to lo g y . O s te o p e n ia (thin bo n e s) is d u e in la rg e p a rt to o s te o p o ro s is as d e fin e d above, a lth o u g h th e re a re o th e r c o n trib u to rs such as m ild v ita m in D d e fic ie n c y o r h y p e rth y ro id is m .
EPIDEMIOLOGY
It is e s tim a te d th a t o v e r 1.3 m illio n o s te o p o ro tic fra c tu re s o c c u r e a c h y e a r in th e U n ite d S ta te s . A p p ro x im a te ly o n e -h a lf o f th e s e fra c tu re s are v e rtebral fra c tu re s , o n e -q u a rte r a re hip fra c tu re s , and one- q u a rte r a re C o lle s ’ fra c tu re s (2). P e lv ic an d hip fra c tu re s a re a s s o c ia te d w ith in c re a s e d m o rta lity, a lth o u g h c o n d itio n s o th e r th a n th e fra c tu re its e lf m ay a c c o u n t fo r m o s t o f th e d e a th s (4 ).T h e risk of all fra c tu re s rises d ra m a tic a lly w ith ag e b u t o s te o p o ro tic fra c tu re s a re not lim ite d to th e e ld e rly.
T h e n u m b e r of w o m e n at risk fo r fra c tu re b e c a u s e of ra d io g ra p h ic o s te o p o ro s is (d e fin e d as b o n e m ineral d e n s ity m o re th a n 2 SD b e lo w th e m ean o f young w o m e n ) is m uch h ig h e r th a n th e n u m b e r of w o m e n w h o a c tu a lly h a v e fra c tu re s .A p p ro x im a te ly 30 p e rc e n t of w o m e n o v e r th e ag e o f 50 h a v e low b o n e m ass, and th e n u m b e rs in c re a s e w ith a g e .L o w lu m b a r sp in e bone m in e ra l d e n s ity is p re s e n t in 15 p e rc e n t of w o m e n in th e sixth d e c a d e , and in n e a rly o n e -h a lf of all w o m e n in th e e ig h th an d n inth d e c a d e s .W h e n a m ore strict d e fin itio n o f o s te o p o ro s is (2.5 S D b e lo w th e m ean of y o u n g w o m e n ) is used, th e p re v a le n c e is 13 to 18 p e rc e n t in w o m e n a b o v e ag e 50 years, and 3 to 6 p e rc e n t in m en a b o v e a g e 50 y e a rs (5).
T h e b u rd e n of o s te o p o ro s is is b o rn e d is p ro p o rtio n a lly by w o m e n . A fte r a ge 50, a w o m a n is th re e tim e s m ore likely th a n a m a n to h a v e a v e rte b ra l o r hip fra c tu re (1 6 to 18 v e rs u s 5 to 6 % ) and six tim e s m ore likely to h ave a C o lie s ’ fra c tu re (6). It has b een e s tim a te d th a t as m u ch as 7 5 p e rc e n t o f b o n e lo s t in th e y e a rs after m e n o p a u s e m a y be re la te d to e s tro g e n d e fic ie n c y ra th e r th a n a g e (7).
PATHOGENESIS
O s te o p o ro s is is th e end re s u lt o f y e a rs of b one loss, w h ic h is a lw a y s d u e to a m is m a tc h b e tw e e n bone re s o rp tio n and b o n e fo rm a tio n . B oth b o n e resorption a n d fo rm a tio n a re in c re a s e d in p o s tm e n o p a u s a l
w o m e n (8 ,9 ), h y p e rp a ra th y ro id is m (1 0 ), h y p e rth y ro id is m (1 1 ), a n d m a ln u tritio n . H o w e v e r, re s o rp tio n o u tp a c e s fo rm a tio n in th e s e d is o rd e rs , re s u ltin g in h ig h -tu rn o v e r o s te o p o ro s is . P a tie n ts w ith a n o re x ia n e rv o s a , fo r e x a m p le , te n d to h a v e lo w b o n e d e n s ity , w h ic h is m o re th a n tw o s ta n d a rd d e v ia tio n s b e lo w n o rm a l in 50 % (12). T h e b o n e loss is c a u s e d by low p ro d u c tio n o f bo th e s tro g e n (13) an d in s u lin -lik e g ro w th fa cto r-1 (1 4 ,1 5 ). E xe rc is e a p p e a rs to m in im iz e th e b o n e lo s s in th e s e p a tie n ts and b o n e d e n s ity im p ro v e s w ith re c o v e ry an d re s u m p tio n of n o rm a l m e n s e s (13). T h e m e c h a n is m by w h ic h e s tro g e n lack le a d s to in c re a s e d b o n e loss is n o t w e ll u n d e rs to o d . B oth d ire c t e ffe c ts on o s te o c la s t fu n c tio n an d c h a n g e s in th e re le a s e o f c e rta in c y to k in e s a p p e a r to c o n trib u te . B o n e re s o rp tio n an d fo rm a tio n are re d u c e d in p a tie n ts w ith liv e r d is e a s e ; h o w e v e r, fo rm a tio n is im p a ire d to a g re a te r e x te n t th a n re s o r p tio n , re s u ltin g in lo w - tu r n o v e r o s te o p o r o s is (1 6 ). B o n e re s o r p tio n is a c c e le ra te d a n d fo r m a tio n is s lo w e d b y e x c e s s g lu c o c o r tic o id s . T h is c o m b in a tio n c a n le a d to e x tre m e ly ra p id b o n e loss. C e rta in d ru g s such as h e p a rin , c y c lo s p o rin , m e d ro x y p ro g e s te ro n e a c e ta te , v ita m in A, c e rta in s y n th e tic re tin o id s a nd p e rh a p s w a rfa rin , ca n a ls o c a u s e b o n e loss. M o s t p a tie n ts w ith o s te o p o ro s is , h o w e v e r, d o n o t h a v e a n y o f th e s e p rim a ry d is e a s e s , an d th e ir b o n e lo s s is la rg e ly d u e to tw o fa c to rs : a g e -re la te d b o n e lo s s an d m e n o p a u s e - re la te d b o n e loss.
Age-related bone loss
- A g e -re la te d b o n e loss b e g in s in th e fo u rth o r fifth d e c a d e s , a nd re s u lts in a s lo w loss of c o rtic a l a n d tra b e c u la r b o n e in bo th m e n an d w o m e n (17). T h is lo s s m a y b e p a rtia lly d u e to d e c re a s e d c a lc iu m a b s o rp tio n , an d m a y be s o m e w h a t a tte n u a te d by c a lc iu m s u p p le m e n ta tio n (18).Menopause-related bone loss
- M e n o p a u s e re la te d b o n e loss b e g in s s o o n a fte r th e o n s e t o f e s tro g e n d e fic ie n c y . A ra p id a c c e le ra tio n o f b o n e lo s s is p a rtic u la rly s e e n in tra b e c u la r b o n e (17). A fte r th e m e n o p a u s e , th e o v a rie s in m a n y w o m e n c o n tin u e to s e c re te a sm a ll a m o u n t o f e s tra d io l, w h ile in o th e rs th e re is no e s tra d io l s e c re tio n . W h e n th e s e tw o g ro u p s w e re c o m p a re d a b o u t tw e n ty y e a rs a fte r th e m e n o p a u s e , th o s e w ith u n d e te c ta b le c o n c e n tra tio n s of s e ru m e s tra d io l ha d m o re b o n e loss (19) a nd a re la tiv e risk of v e rte b ra l a nd hip fra c tu re o f 2 .5 c o m p a re d to w o m e n w h o ha d m e a s u ra b le s e ru m e s tra d io l (20). E s tro g e n r e p la c e m e n t th e ra p y , o ro g e s tin s a n d b is p h o s p h o n a te s c a n a tte n u a te th is lo s s (8 ,2 1 -2 3 ). M e n o p a u s e -re la te d b o n e lo s s la s ts fo r a b o u t 10 y e a rs. A fte r th is tim e , th e ra te o f b o n e loss is d im in is h e d to n e a r th e ra te o f a g in g (17).Osteoporosis in men
- G o n a d a l fa ilu re a nd a n d ro g e n in s e n s itiv ity a re a lso risk fa c to rs fo r o s te o p o ro s is in m en (2 4 -2 6 ). A ll m e n w ith o th e rw is e u n e x p la in e do s te o p o ro s is s h o u ld b e a s k e d a b o u t s y m p to m s of h y p o g o n a d is m ( d e c r e a s e d lib id o , im p o te n c e a n d te s tic u la r a tr o p h y ) a n d th e s e ru m te s to s te r o n e c o n c e n tra tio n s h o u ld b e m e a s u re d . In a d d itio n to te s to s te ro n e , e s tro g e n h a s an im p o rta n t e ffe c t upon b o n e m e ta b o lis m in m e n . In o n e s tu d y , b o n e d e n s ity at all s k e le ta l s ite s in m e n o v e r th e a g e o f 65 w a s p o s itiv e ly c o rr e la te d w ith h ig h e r s e ru m e s tra d io l c o n c e n tra tio n s , e v e n a fte r a d ju s tm e n ts fo r w e ig h t an d s e ru m s e x -h o rm o n e b in d in g g lo b u lin c o n c e n tra tio n s (27). L o w b o n e d e n s ity ha s a ls o b e e n d e s c rib e d in p a tie n ts w ith m a rk e d e s tro g e n d e fic ie n c y d u e to a d e fe c t in th e e s tro g e n re c e p to r g e n e , an d e s tro g e n d e fic ie n c y d u e to a lo s s -o f-fu n c tio n m u ta tio n in th e a r o m a ta s e g e n e (2 8 ,2 9 ). S im ila rly , s tu d ie s in p o s tm e n o p a u s a l w o m e n s u g g e s t th a t lo w s e ru m a n d ro g e n c o n c e n tra tio n s m a y c o n trib u te to th e b o n e lo s s a s s o c ia te d w ith e s tro g e n d e fic ie n c y (30).
Genetic factors
- G e n e tic fa c to rs m o s t lik e ly p lay a c o n trib u to ry role in b o n e d e n s ity s ta tu s . A m o n g th e g e n e s th a t h a v e b e e n s tu d ie d is th e v ita m in D re c e p to r g e n e . A lle lic v a ria tio n in th is g e n e c o u ld th e o re tic a lly a ffe c t th e a b ility to b in d v ita m in D ( d ire c tly o r d u e to v a r ia tio n in th e n u m b e r o f r e c e p to rs ), th e r e b y p re d is p o s in g s o m e p a tie n ts to re d u c e d b o n e m in e ra l d e n s ity and la te r,o s te o p o ro s is (31). A n o th e r g e n e th a t ha s b e e n a s s o c ia te d w ith b o n e d e n s ity is C O L IA 1 , th e g e n e fo r c o lla g e n ty p e la lp h a l, a b o n e m a trix p ro te in . C O LIA 1 p o ly m o rp h is m h a s b e e n d e te c te d in 1700 p o s tm e n a p a u s a l w o m e n w ith re d u c e d b o n e d e n s ity (32). A n in c re a s e d fra c tu re ris k m a y a ls o b e d u e to p re v io u s fr a c tu re s , c ig a r e tte s m o k in g , m a la b s o rp tiv e g a s tr o in te s tin a l d is e a s e s in c lu d in g c y s tic fib ro s is , p re v io u s h y p e rth y ro id is m , s e d e n ta ry life s ty le , low b o d y w e ig h t o r w e ig h t lo s s , a n d a n x io ly tic , a n tic o n v u ls a n t, o r n e u ro le p tic d ru g s (3 3 -3 6 ).TYPES OF OSTEOPOROSIS
T h e b im o d a l n a tu re o f p o s tm e n a p a u s a l b o n e loss w a r r a n ts a d is tin c tio n b e tw e e n tw o d iffe r e n t s y n d ro m e s : ty p e I a n d ty p e II o s te o p o ro s is . T y p e I o s te o p o ro s is is d u e to ra p id tra b e c u la r b o n e lo s s a fte r m e n a p a u s e . Its p rim a ry c lin ic a l m a n ife s ta tio n s are d is ta l fo re a rm a n d p a in fu l v e rte b ra l c o m p re s s io n fra c tu re s 10 to 2 0 y e a rs a fte r m e n a p a u s e . S lo w c u m u la tiv e lo s s o f b o th c o rtic a l a n d tra b e c u la r b o n e c a u s e s ty p e II o s te o p o ro s is . Its p rim a ry m a n ife s ta tio n s a re h ip fr a c tu r e s a n d p a in le s s v e r te b r a l w e d g e fra c tu re s a t th e a g e s o f 70 to 90. T h e v e rte b ra l w e d g e fra c tu re s a re p a in le s s b e c a u s e b o n e lo s s is s lo w an d th e fra c tu re s a re g ra d u a l. M a n y p a tie n ts m a y be hard to c la s s ify .
CLINICAL M AN IFESTATIO N S
O s te o p o ro s is ha s no c lin ic a l m a n ife s ta tio n s until th e re is a fra c tu re . In c o m p a ris o n , p ain is co m m o n in o s te o m a la c ia . V e rte b ra l fra c tu re is th e m o s t co m m o n c lin ic a l m a n ife s ta tio n o f o s te o p o ro s is . A b o u t tw o -th ird s o f th e s e fra c tu re s a re a s y m p to m a tic and th e y are d ia g n o s e d a s an in c id e n ta l fin d in g on c h e s t x-ray. O s te o p o ro tic fra c tu re c a n le a d to th e a c u te o n s e t of p ain, ty p ic a lly o c c u rin g d u rin g ro u tin e a ctivitie s, such as b e n d in g an d p u llin g . T h e a c u te pain d im in is h e s in s e v e ra l w e e k s an d is re p la c e d by a c h ro n ic dull pain w h ic h ca n p e rs is t fo r a p ro lo n g e d tim e in s o m e p a tie n ts . S u c c e s s iv e c ru s h fr a c tu re s c a n c a u s e th o ra c ic (d o rs a l) k y p h o s is w ith h e ig h t loss and the d o w a g e r’s h u m p (3). P a tie n ts no te th a t th e y no longer h a v e a w a is t. T h e y m a y c o m p la in of m u s c u la r neck p ain, s in c e th e y h a v e to e x te n d th e ir n e cks in o rd e r to lo o k fo rw a rd . M u ltip le v e rte b ra l c o m p re s s io n fra c tu re s lead to d is c o m fo rt in th e hips, e s p e c ia lly in th e a re a of th e s u p e rio r ilia c cre st. T h is sym p to m is d u e to a re d u c tio n in th e n o rm a l d is ta n c e b e tw e e n th e b o tto m of th e rib c a g e a n d th e to p o f th e iliac cre s ts ; th e rib c a g e m a y b o u n c e on th e iliac c re s ts c a u s in g pain. D yspnea a n d g a s tr o in te s tin a l c o m p la in ts (e a rly s a tie ty ,c o n s tip a tio n ) m a y a rise.
H ip fra c tu re s a re re la tiv e ly c o m m o n in o s te o p o ro s is , a ffe c tin g 15 % o f w o m e n an d 5 % of m en by 80 y e a rs o f ag e . D ista l ra d iu s fra c tu re s (C o lle s) m a y a lso o c c u r (37).
RADIOGRAPHIC FEATURES
P lain ra d io g ra p h s s h o w d e te c ta b le c h a n g e s w hen b o n e loss e x c e e d s 30 p e rc e n t. T h e v e rte b ra l b o d ies m a y a p p e a r as e m p ty sh e lls. T h in n in g and loss of tra b e c u la r p a tte rn a ls o o c c u rs in th e fe m o ra l neck.
In th e s p in e , an e a rly m a n ife s ta tio n is “c o d fis h in g ” ; this o c c u rs w h e n th e in te rv e rte b ra l d is c c a u s e s a ce n tra l d e p re s s io n in th e m id d le o f th e v e rte b ra l body. S pinal o s te o p o ro s is ca n a ls o lead to c o m p re s s io n fra c tu re s or w e d g e fr a c tu re s . A n te rio r w e d g in g is u s u a l and p o s te rio r w e d g in g is u n c o m m o n . W e d g e fra c tu re s m ay c a u s e fo rw a rd -th ru s tin g th o ra c ic k y p h o s is . T h o ra c ic k y p h o s is ca n a ls o re s u lt fro m m is a lig n m e n t of p e rfe c tly re c ta n g u la r, n o n o s te o p o ro tic v e rte b ra l b o d ie s . T h is im p o rta n t d is tin c tio n is m a d e by la te ra l s p in e o r c h e s t x -ra y (17).
LABORATORY STUDIES
E v a lu a tio n s h o u ld in c lu d e a c h e m is tr y p ro file , c o m p le te b lo o d c o u n t, an d s e ru m th y ro tro p in (T S H ) m e a s u re m e n t. N o rm a l s e ru m b ic a rb o n a te , c a lciu m ,
T S H a n d c re a tin in e v a lu e s e x c lu d e p o te n tia lly tre a ta b le c o n d itio n s s u c h as m e ta b o lic a c id o s is , h y p e rp a ra th y ro id is m , h y p e rth y ro id is m a nd renal in s u ffic ie n c y . N o rm a l s e ru m c a lc iu m , p h o s p h a te , a lb u m in and a lk a lin e p h o s p h a ta s e va lu e s m itigate a g a in s t o s te o m a la c ia , w h ile a n o rm a l b lood c o u n t and c a lc iu m c o n c e n tra tio n m a k e s m y e lo m a unlikely. The serum a lk a lin e p h o s p h a ta s e c o n c e n tra tio n m ay be high in p a tie n ts w ith re c e n t h e a lin g fra ctu re s. Thus, an iso la te d high v a lu e in a p a tie n t w ith a re ce n t fra c tu re is o f lim ited s ig n ific a n c e .
T h e s e ru m te s to s te ro n e c o n c e n tra tio n sh o u ld be m e a s u re d in m en w ith o s te o p o ro s is , p a rtic u la rly if th e re is d im in is h e d libido, im p o ta n c e , or te s tic u la r a tro p h y (38).
T h e serum c o n c e n tra tio n o f 2 5 -h y d ro x y v ita m in D and p a ra th y ro id h o rm o n e (P T H ) sh o u ld be m e a su re d if the p a tie n t is e ld e rly w ith p o o r v ita m in D in ta ke or if there is a h is to ry of g a s tro in te s tin a l d is e a s e (such as m a la b s o rp tio n o r g a s tre c to m y ), liv e r d is e a s e , or a n tic o n v u ls a n t th e ra p y . V ita m in D d e fic ie n c y is a s s o c ia te d w ith low s e ru m 2 5 -h y d ro x y v ita m in D and high serum P TH c o n c e n tra tio n s d u e to se c o n d a ry h y p e rp a ra th y ro id is m .
U rin a ry c o rtis o l e x c re tio n o r an o v e rn ig h t d e x a m e th a s o n e s u p p re s s io n te s t sh o u ld be p e rfo rm e d if C u s h in g 's s y n d ro m e is s u s p e c te d . T h e s e ru m PTH c o n c e n tra tio n sh o u ld be m e a s u re d in th e p re s e n c e o f h y p e rc a lc e m ia o r h y p e rc a lc iu ria . A s e ru m an d u rin e p ro te in e le c tro p h o re s is m u s t be o b ta in e d if m u ltip le m y e lo m a is being c o n s id e re d (37).
T he W o rld H e a lth O rg a n iz a tio n has d e fin e d norm al b o n e d e n s ity as a v a lu e w ith in o n e sta n d a rd d e via tion o f th e y o u n g a d u lt m ean. B o n e m in e ra l d e n s ity (B M D ) in a n y a d u lt th a t is b e tw e e n 1 an d 2 .5 s ta n d a rd d e v ia tio n s b e lo w th e m e a n is d e fin e d as o ste o p e n ia , and v a lu e s m o re th a n 2 .5 s ta n d a rd d e v ia tio n s below th e m ean is d e fin e d as o s te o p o ro s is an d is a s s o c ia te d w ith s k e le ta l fra g ility ; th is le v e l is c o n s id e re d to re p re s e n t th e fra c tu re th re s h o ld . T h e lo w e r th e bone m ass, th e g re a te r is th e te n d e n c y to fra c tu re (2).
T h e re a re s e v e ra l d iffe re n t m e th o d s u sed to assess b o n e d e n s ity : s in g le an d d ual p h o to n a b s o rp tio m e try , d u a l x -ra y a b s o rp tio m e try , q u a n tita tiv e c o m p u te d to m o g ra p h y , u ltra s o n o g ra p h y a n d ra d io g ra p h ic a b s o rp tio m e try a re s u c h m e th o d s . D ual x -ra y a b s o rp tio m e try (D X A ) g iv e s an a c c u ra te and pre cise e s tim a te o f B M D , an d is th e re fo re th e m e th o d of c h o ic e (39).
B o n e d e n s ito m e tr y is in d ic a te d w h e n e v e r a d e te rm in a tio n o f b o n e d e n s ity w ill h e lp g u id e th e th e ra p e u tic d e c is io n -m a k in g p ro c e s s . T h is c a n o c c u r in s e v e ra l s e ttin g s : ' I t c a n b e p e rfo rm e d a ro u n d th e tim e o f m e n o p a u s e to h e lp g u id e a d e c is io n a b o u t e s tro g e n re p la c e m e n t th e ra p y . 'P a t ie n t s ta k in g lo n g -te r m g lu c o c o r tic o id th e r a p y s h o u ld h a v e b a s e lin e a n d s e ria l m e a s u re m e n ts of b o n e d e n s ito m e try to h e lp g u id e th e ra p e u tic o p tio n s .
'P a t ie n t s w ith a s y m p to m a tic p rim a ry h y p e rp a ra th y ro id is m w h o m ig h t b e m a n a g e d m e d ic a lly s h o u ld h a v e in itia l a n d s e ria l m e a s u re m e n ts .
MEDICAL THERAPY
O ra l c a lc iu m s u p p le m e n ts , h o rm o n e re p la c e m e n t th e r a p y , s e le c tiv e e s tr o g e n r e c e p to r m o d u la to rs (S E R M s ), c a lc ito n in , c a lc itrio l, b is p h o s p h o n a te s and s o d iu m flu o rid e h a v e all b e e n u s e d in th e tre a tm e n t of o s te o p o ro s is .
Calcium Supplements
- T h e e ffe c t o f c a lc iu m s u p p le m e n ta tio n on b o n e m a s s a n d v e rte b ra l fra c tu re ra te in e s ta b lis h e d o s te o p o ro tic s ta te s is n o t w e ll s tu d ie d . S o m e s tu d ie s s u g g e s t th a t c a lc iu m s u p p le m e n ta tio n in p e rim e n o p a u s a l fe m a le s d o e s d e c re a s e th e ra te o f b o n e lo s s w h e n g iv e n in d o s e s o f 1 0 0 0 -1 5 0 0 m g /d a y , e s p e c ia lly in s u b je c ts w ith low c a lc iu m in ta k e s (4 0 ). A c o m b in a tio n o f c a lc iu m s u p p le m e n ts a n d e x e rc is e ha s a ls o p ro v e n e ffe c tiv e in re d u c in g s k e le ta l b o n e lo s s ra te s in p o s tm e n o p a u s a l fe m a le p o p u la tio n s .Hormone replacement therapy
- E s tro g e n is an “a n tire s o rp tiv e ” a g e n t w h ic h in h ib its b o n e re s o rp tio n by d e c re a s in g th e fre q u e n c y o f a c tiv a tio n o f th e b o n e re m o d e lin g c y c le . In th e e a rly s ta g e s o f m e n o p a u s e , w h e n b o n e tu rn o v e r is in c re a s e d , it is e x p e c te d to be m o s t e ffic ie n t. T h e u s u a l s ta rtin g d o s e is 0 .6 2 5 m g of c o n ju g a te d e q u in e e s tro g e n o r 0 .0 5 m g o f tra n s d e rm a l e s tro g e n , an d th e y m a y b e g iv e n in c o m b in a tio n w ith p ro g e s te ro n e . U n w a n te d s y m p to m s (b r e a s t te n d e r n e s s ,s p o ttin g ,p e lv ic d is c o m fo r t a n d m o o d c h a n g e s ) re la te d to H R T h a v e lim ite d th e n u m b e r o f p e rs o n s w h o e x p e rie n c e its b o n e -s p a rin g e ffe c ts (41).Selective Estrogen Receptor Modulators (SERMs)
T h e s e c o m p o u n d s in te ra c t w ith th e e s tro g e n re c e p to r b u t h a v e tis s u e - s p e c ific a c tiv itie s . F o r e x a m p le , ra lo x ife n e , w h ic h is a m e m b e r o f th is fa m ily , a c ts as an e s tro g e n a n ta g o n is t o n th e u te ru s a n d b re a s t b u t d is p la y s e s tro g e n -a g o n is tic a c tiv itie s on b o n e m a s s an d lipids. T h is c la s s o f d ru g s m a y in c lu d e 1) v a rio u s
a g e n ts p re v io u s ly k n o w n a s a n tie s tro g e n s , s u c h a s 16- e p ie s tr io l, e th a m o x y tr ip h e to l, c lo m ip h e n e , a n d ta m o x ife n ; 2) a 19 - n o r te s to s te r o n e d e r iv a tiv e , tib o lo n e ; 3) ra lo x ife n e a n d its a n a lo g s , s u c h a s LY 1 1 7 0 1 8 ; a n d 4) n e w e r tr ip h e n y le th y le n e d e riv a tiv e s , s u c h a s d r o lo x ife n e , to r e m ife n e , id o x ife n e , a n d le v o rm e lo x ife n e . V a rio u s d o s e s o f ra lo x ife n e a n d e le m e n ta l c a lc iu m h a v e d e c re a s e d b o n e tu rn o v e r m a rk e rs a n d s ig n ific a n tly in c re a s e d b o n e m in e ra l d e n s ity (42).
Calcitonin
- L ik e e s tro g e n , c a lc ito n in in h ib its b o n e re s o rp tio n a n d s lo w s d o w n th e ra te o f b o n e loss. In p a tie n ts w ith in c re a s e d b o n e tu rn o v e r, th e re s p o n s e is b e tte r th a n p a tie n ts w ith lo w tu r n o v e r . T h e re c o m m e n d e d d o s e is 100 U s u b c u ta n e o u s ly d a ily . In te rm itte n t p u ls e -d o s e re g im e n s h a v e a ls o b e e n u s e d w ith d o c u m e n ta tio n o f in c re a s e d b o n e m a s s a nd d e c re a s e d fra c tu re in c id e n c e . C a lc ito n in h a s in h e re n t a n a lg e s ic p ro p e rtie s a n d c a n b e re c o m m e n d e d in th e e a rly p o s tfra c tu re p e rio d b e c a u s e o f th is e ffe c t. S id e e ffe c ts (flu s h in g , n a u s e a ) a n d th e d e v e lo p m e n t of a n tib o d ie s m a y lim it its u s e (43).Calcitriol
- C a lc itrio l, in a d o s e o f 0 .2 5 (g /d a y , ha s b e e n s h o w n to re d u c e th e v e rte b ra l fra c tu re rate c o m p a re d w ith a g ro u p o f p a tie n ts ta k in g c a lc iu m a lo n e . In s o m e in s ta n c e s , in c re m e n ts in b o n e m a s s o f 1-2 % /a n n u m h a v e b e e n re c o rd e d . It h a s a ls o b e e n u s e d in th e tre a tm e n t o f s te ro id -in d u c e d o s te o p o ro s is . B e c a u s e c a lc itrio l is th e m o s t p o te n t m e ta b o lite of v ita m in D, it d o e s in c r e a s e in te s tin a l c a lc iu m a b s o rp tio n , o fte n re s u ltin g in h y p e rc a lc iu ria a n d /o r h y p e rc a lc e m ia . P a tie n ts s h o u ld b e m o n ito re d e v e ry 6- 8 w e e k s fo r d e v e lo p m e n t o f th e s e b io c h e m ic a l a b n o rm a litie s (44).Bisphosphonates
- T h is g r o u p o f c o m p o u n d s in c lu d e s e tid r o n a te , a le n d r o n a te , p a m id ro n a te , tilu d ro n a te , ris e d ro n a te a n d ib a n d ro n a te . E ffic a c y o f e tid ro n a te (4 0 0 m g /d a y , fo r tw o w e e k s e v e ry 3 m o n th s , w ith s u p p le m e n ta l c a lc iu m ) h a s b e e n d e m o n s tra te d in p o s tm e n o p a u s a l w o m e n a n d p a tie n ts w ith g lu c o c o rtic o id -in d u c e d o s te o p o ro s is . C y c lic e tid ro n a te h a s a ls o b e e n u s e d in c o m b in a tio n w ith e s tro g e n fo r b o th p re v e n tio n a n d tr e a tm e n t o f o s te o p o ro s is (45). T h e lo n g -te rm e ffic a c y o f a le n d ro n a te (1 0 m g /d a y ) ha s b e e n d o c u m e n te d in p o s tm e n o p a u s a l o s te o p o ro s is . A m e ta -a n a ly s is h a s s h o w n a re d u c tio n in v e rte b ra l an d n o n v e rte b ra l fra c tu re in c id e n c e (4 6 ). A le n d ro n a te is u s u a lly w e ll to le ra te d , b u t e s o p h a g itis a n d e s o p h a g e a l u lc e rs c a n o c c u r.Sodium fluoride
- T h is c o m p o u n d is u s e d in d o s e s b e tw e e n 5 0 -7 5 m g /d a y fo r th e tr e a tm e n t o f p o s tm e n o p a u s a l o s te o p o ro s is . A lth o u g h th e in c re a s e in s p in a l b o n e m a s s a p p ro x im a te s 8 % /y e a r, th e re is little e v id e n c e t h ^ t th is in c r e a s e tr a n s la te s to are d u c tio n in v e rte b ra l fr a c tu re s . M o ro v e r, it is a s s o c ia te d w ith s ig n ific a n t g a s tro in te s tin a l d istre ss an d a p a in fu l lo w e r e x tre m ity s y n d ro m e . B e ca u se of th e s e fa c to rs , it has not b e e n v e ry p o p u la r in the tre a tm e n t o f o s te o p o ro s is (37).
V a rio u s c o m b in a tio n s an d tre a tm e n t re g im e n s of th e se d ru g s , as w e ll as n e w e r c o m p o u n d s such as syn th e tic p a ra th y ro id h o rm o n e , a re c u rr e n tly u n d e rg o in g e x te n s iv e c lin ic a l tria ls . If th e ir s a fe ty and e ffic a c y are e s ta b lis h e d , th e ir use w ill be w id e s p re a d .
REFERENCES
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2 8 . S m ith EP, B o y d J , F ra n k GR, e t a l. E s tro g e n r e s is ta n c e c a u s e d b y a m u ta tio n in th e e s tro g e n - r e c e p t o r g e n e in a m a n . hi E n g l J M e d 1 9 9 4 ;3 3 1 :1 0 5 6 - 1 0 6 2 . 2 9 . C a r a n i C, Q in R, S im o n i M, e t a l. E ffe c t o f te s to s te r o n e a n d e s tra d io l in a m a n w ith a ro m a ta s e d e fic ie n c y , hi E n g l J M e d 1 9 9 7 ;3 3 7 :9 1 -9 5 . 3 0 . S le m e n d a C, L o n g c o p e C, P e a c o c k M, e t al. S e x s te ro id s , b o n e m a s s a n d b o n e lo s s . J C lin In v e s t 1 9 9 6 ;9 7 :1 4 -2 1 .
3 1 . Riggs BL. V ita m in D -re c e p to r g e n o ty p e s a n d b o n e d e n s ity , hi E n g l J M e d 1 9 9 7 ;3 3 7 :1 2 5 - 1 2 6 .
3 2 . U itte rlin d e n AG , B u rg e r ft, H u a n g Q, e t al. R e la tio n o f a lle le s o f th e c o lla g e n ty p e la I g e n e to b o n e d e n s ity a n d th e r is k o f o s te o p o r o tic fr a c tu r e s in p o s t m e n o p a u s a l w o m e n . hi E n g l J M e d 1 9 9 8 ;3 3 8 :1 0 1 6 - 1 0 2 1 . 3 3 . H o p p e r J L , S e e m a n E. T he b o n e d e n s ity o f fe m a le tw in s d is c o rd a n t f o r to b a c c o use. hl E n g l J M e d 1 9 9 4 ;3 3 0 :3 8 7 - 3 9 2 . 3 4 . B ja rn a s o n 1, M a c p h e rs o n A, M a c k in to s h C, e t al. R e d u c e d b o n e d e n s ity in p a tie n ts w ith in fla m m a to r y b o w e l d is e a s e . G u t 1 9 9 7 ;4 0 :2 2 8 -2 3 3 .
3 5 . L iu B, A n d e rs o n G, M ittm a n hi, e t at. Use o f s e le c tiv e s e r o to n in - r e u p t a k e in h ib it o r s o r t r ic y c lic a n tid e p re s s a n ts a n d r is k o f h ip fr a c tu r e s in e ld e r ly p e o p le . L a n c e t 1 9 9 8 ;3 5 1 :1 3 0 3 - 1 3 0 7 . 3 6 . E n s ru d RE, L ip s c h u tz MP, C a u le y JA. B o d y s iz e a n d h ip fr a c tu r e r is k in o ld e r w o m e n : A p r o s p e c tiv e s tu d y . A m J M e d 1 9 9 7 ,1 0 3 :2 7 4 - 2 8 0 . 3 7 . R le e r e k o p e r M, A v io li LV. E v a lu a tio n a n d tr e a tm e n t o f p o s tm e n o p a u s a l o s te o p o ro s is , ln : F a v u s MJ, Ed. P r im e r o n th e M e t a b o lic B o n e D is e a s e s a n d D is o rd e rs o f M in e ra l M e ta b o lis m 2 n d ed. L ip p in c o tt- R aven, P h ila d e lp h ia , 1 9 9 3 :2 2 3 - 2 2 9 . 3 8 . J a c k s o n JA . O s te o p o r o s is in m e n . In : F a v u s MJ, Ed. P r im e r o n t h e M e t a b o lic B o n e D is e a s e s a n d D is o r d e r s o f M in e r a l M e ta b o lis m . 2 n d ed. L ip p in c o tt-R a v e n , P h ila d e lp h ia , 1 9 9 3 :2 5 5 - 2 5 8 . 3 9 . G ê n a n t HR, E n g e lk e R, F u e rs t T, e t a l. h lo n in v a s iv e a s s e s m e n t o f b o n e m in e r a l a n d s tr u c tu r e : S ta te o f th e a rt. J B o n e M in e r Res 1 9 9 6 ; 1 1.7 0 7 - 7 1 2 . 4 0 . D a w s o n -H u g h e s B, D a lla i GE, R r a ll EA, e t al.
C o n t r o lle d t r i a l o f t h e e f f e c t o f c a lc iu m s u p p le m e n t a t io n o n b o n e d e n s it y in p o s tm e n o p a u s a l w o m e n , hi E n g l J M e d 1 9 9 0 ; 3 2 3 :8 7 8 - 8 8 3 . 4 1 . R e c k e r RR, D a v ie s RM, D o w d RM, H e a n y RP. The e f f e c t o f lo w - d o s e c o n t in u o u s e s tr o g e n a n d p ro g e s te ro n e th e r a p y w ith c a lc iu m a n d v ita m in D o n b o n e in e ld e r ly w o m e n . A n n In t M e d 1 9 9 9 ; 1 3 0 :8 9 7 -9 0 4 . 4 2 . R h o u id h u n k it W, S h o b a c k DM. C lin ic a l e ffe c ts o f r a lo x ife n e h y d r o c h lo r id e in w o m e n . A n n In t M e d 1 9 9 9 ;1 3 0 :4 3 1 - 4 3 9 . 4 3 . A v io li LV. H e te ro g e n e ity o f o s te o p o r o tic s y n d ro m e s a n d th e re s p o n s e t o c a lc it o n in th e ra p y . C a lc ific T issu e I n t 1 9 9 1 ;4 9 (S u p p l 2 ): S I 6 -1 9 . 4 4 . T ily a rd MW, S p e a rs GFS, T h o m p s o n J , D o v e y S. T re a tm e n t o f p o s tm e n o p a u s a l o s te o p o r o s is w ith c a lc it r io l o r c a lc iu m , hi E n g l J M e d 1 9 9 2 ; 3 2 6 :3 5 7 - 3 6 1 . 4 5 . W im a la w a n s a SJ. C o m b in e d th e r a p y w ith e s tro g e n a n d e tid r o n a te h a s a n a d d it iv e e ffe c t o n b o n e m in e r a l d e n s ity in th e h ip a n d v e rte b ra e : F o u r y e a r r a n d o m iz e d s tu d y . A m J M e d 1 9 9 5 :9 9 :3 6 -4 2 . 4 6 . R a r p f DB, S h a p iro DR, S e e m a n , e t al. P r e v e n tio n o f
n o n v e r t e b r a l f r a c t u r e s b y a le n d r o n a t e . A m e ta a n a ly s is . J A M A 1 9 9 7 ; 2 7 7 :1 1 5 - 1 2 1 .
