Acid Induced Osteoporosis

7/27/2019 Acid Induced Osteoporosis

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Acid- induced Osteoporos i s : An Exper imenta l Mode l o f Human Osteo-porosis

U . S . B A R Z E L

S U M M A R YA d u l t a n i m a ls , m a l e o r f em a l e , r e a c t t o a m m o n i u m c h l o r i d e i n g e s ti o n w i t h an o n - h o r m o n a l , g e n e r al iz e d , s l o w b u t p r o g re s s iv e a n d u n r e l e n t i n g m o b i l i z a t i o n o f b o n ea n d d e v e l o p o s t e o p o r o s i s w h i c h s e e m s i n d is t in g u i s h ab l e i n a ll p a r a m e t e r s m e a s u r e df r o m h u m a n o s t e o p o r o s is . ( Ta b l e I ).

Table L

C o m p a r i s o n o f H u m a n O s t e o p o r o s i s a n d E x p e r i m e n t a l ( A c i d - in d u c e d ) O s t e o p o r o s is .

P a r a m e t e r H u m a n o s t eo p o r o s is A n i m a l m o d e l

B l o o d c a l ci u m & p h o s p h o r u sB o n e h i s t o l o g yB o n e m i c r o r a d io g r a p h y

B o n e p e r c e n t a s hB o n e c a lc i u m c o n t e n t

B o n e c r y s t a l l o g r a p h y

n o r m a l n o r m a lo s t e o p o r o s i s o s t e o p o r o s i si n c r e a se d r e s o r p t i o n i n c re a s e d r e s o r p t i o nn o r m a l f o r m a t i o n n o r m a l f o r m a t i o nn o r m a l n o r m a ld i m i n i s h e d d i m i n i s h e d

n o r m a l n o r m a l

O s t e o p o r o s i s c a n b e d e f i n e d a s a c o n d i t i o n i n w h i c h g e n e r a l iz e d ,p r o g re s si v e d i m i n u t i o n i n b o n e d e n s i t y r e n d e r s b o n e s i n c re a s in g l y v u ln e r -a b l e t o f r a c t u r e . C l i n ic a ll y, o s t e o p o r o s i s h a s a s l o w n a t u r a l h i s t o r y a n d a nu n p r e d i c t a b l e c o u r s e : i t is v i r t u a ll y i m p o s s i b l e t o p r e d i c t i f a n d w h e n a n yg i v e n p a t i e n t is a b o u t t o h a v e a f r a c t u r e ( 2 1 ) , a n d i n s o m e c a se s t h ep r o g r e s s i o n o f t h e d i se a s e s e e m s t o h a v e b e e n a r r e s t e d a l t o g e t h e r ( 1 9 ) .

T h i s s l o w a n d u n p r e d i c t a b l e n a t u r e o f o s t e o p o r o s i s m a k e s i t d e s ir a b le t ou s e e x p e r i m e n t a l a n i m a l m o d e l s i n i t s s t u d y. T h e p r e s e n t p a p e r w i ll

M e t a b o l i c E n d o c r i n e L a b o r a t o r y, D e p a r t m e n t o f M e d i ci n e, M o n t e f i o r e H o s p i t a l a n dMed i ca l Cen t e r, A l b e r t E i n s t e i n Co l l eg e o f Med i c i n e , B ro n x , N ew Y o rk .


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s u m m a r i z e a v a il ab le i n f o r m a t i o n o n t h e m o d e l o f a c id - i n d u c e d o st e o -poros i s (12 , 3 , 4 , 5 , 6 ) .

T H E O R E T I C A L C O N S I D E R AT IO N S A N D M E C H A N IS M S

S i n c e t h e e n d o f t h e l as t c e n t u r y, b o n e h a s b e e n r e c o g n i z e d t o c o n t a i nla rg e a m o u n t s o f a l k a li n e s alt s a n d h a s b e e n t h o u g h t l i k e ly t o p a r t i c ip a t ei n t h e m a i n t e n a n c e o f a c i d b as e b a l a n c e o f t h e o rg a n is m . T h e f a ct t h a td u r i n g a c i d l o a d i n g u r i n a ry c a l c i u m e x c re t i o n a l w a y s i n c r e a s e s g a v es u p p o r t t o t h i s i d e a ( 2 ) . R e c e n t s t u d i e s i n n o r m a l m a n ( 1 4 , 1 5 ) , i n r e n a l

a c id o s i s (1 0 , 1 6 ) , a n d i n s t a rv a t i o n a c i d o s is ( 1 8 ) g a v e a d d i t i o n a l s u p p o r t t ot h e c o n c e p t t h a t b o n e w a s m o b i l i z e d i n a c id l o a d i n g a n d it s s al ts m a d ea v ai la b le t o a u g m e n t t h e b u f f e r i n g c a p a c i t y o f t h e e x t r a c e ll u l ar f l u id .

I n 1 9 6 9 w e s u g g e s t e d , o n t h e b a s i s o f e x p e r i m e n t a l o b s e r v a t i o n s , t h a tc e ll ul ar m e c h a n i s m s i n v o lv e d w i t h b o n e f o r m a t i o n a n d b o n e r e s o r p t i o nw e re r e s p o n s i v e t o c h a n g e s in a c i d b a s e b al a n ce " m i c ro ra d i o g ra p h i c s t u d i e sd e m o n s t r a t e d t h a t t h e c h r o n i c i n g e st io n o f a m m o n i u m c h l o r id e c a u s ed a ni n cr e as e i n b o n e r e s o r p t i o n s u r fa c e s w i t h o u t c h a n g e in b o n e f o r m a t i o ns u r f ac e s , a n d , c o n v e r s e l y, t h e c h ro n i c i n g e s t i o n o f a n a l k al i s o l u t i o nc a u s e d a n i n c r ea s e i n b o n e f o r m a t i o n s u rf a ce s w i t h o u t c h a n g e in b o n er e s o r p t i o n s u rf a ce s (4 ). D e l l in g a n d D o n a t h ( 9) d e m o n s t r a t e d b ye l e c t r o n m i c r o s c o p y t h a t t h e b o n e r e s o r p t i o n w h i c h o c c u r s as a d i r e ctc o n s e q u e n c e o f t h e d i e t a r y i n g e s t io n o f e x c es s a c i d is i n d e e d m e d i a t e d b yb o n e c ells . T h e y d e m o n s t r a t e d t h a t o s t e o c l as t s a n d o s t e o c y t e s w e r ea c t iv a t e d i n a c id l o a d e d a n i m a ls e v e n i n t h e a b s e n c e o f t h e p a r a t h y r o i dg la n ds . A c i d - i n d u c e d b o n e r e s o r p t i o n w a s s h o w n b y R e e d a n d B e c k t o b ei n d e p e n d e n t o f g a s t r o in t e s t in a l a n d r e n a l f a c t o rs a n d w a s o b s e r v e d i na n i m a l s a f t e r n e p h r e c t o m y a n d a f t e r r e m o v a l o f t h e e n t i re G I t r a c t ( 1 7 ) .Cuis in ie r-Gle izes et al . a ls o f o u n d t h a t a m m o n i u m c h lo r i d e i n g e s ti o nc a u s e d b o n e r e s o r p t i o n i n t h e p r e s e n c e a n d in t h e a b s e n ce o f t h ep a r a t h y r o i d g l an d s ( 8 ). T h i s g r o u p , h o w e v e r, d i d n o t f i n d h i s t o lo g i ce v i d e n c e o f c e l lu l a r m e d i a t i o n o f t h is r e s p o n s e . T h e y b e li ev e t h a t t h er e s o r p t i o n o f b o n e is n o t m e d i a t e d b y c ells a n d a ls o t h a t b o n e f o r m a t i o nis d e p r e ss e d in a m m o n i u m c h l o r id e f e d a n im a ls .

T h e o b s e r v a t i o n s c i t e d a b o v e f u r t h e r s t r e n g t h e n t h e h y p o t e s i s t h a tr e s o r p t i o n o f b o n e is ab o n a f i d e p h y s i o lo g i c c o m p e n s a t o r y r e s p o n s e t o

t h e i n g e s t i o n o f a c id .


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T H E E X P E R I M E N TA L M O D E L

A d u l t a n im a l s g i v en a m m o n i u m c h l o r i d e s o l u t io n a s th e i r d r i n k i n g f lu i d ,o r f e d a m m on i um c h l o r i d e i n t he d i e t , d e ve l op h i s to l og i c o s t e opo r os i s(12 , 4 , 5 , 9 , 8 ) , wi th a ra t io o f os t eob las t s to os t eoc las t s comparab le tot h a t o f c o n t r o l a n i m a l s ( 8) . A m m o n i u m c h l o r i d e i n g e s ti o n d o e s n o t a f f e c tt he l e ng t h o r v o l um e o f t he f e m ur ( 4 , 5, 6 ) . T h e r e is a de c re a se i n fe m or a lde ns i t y a s m e a su r e d g r a v i m e t r ic a l ly, by Ar c h i m e de s ' p r i nc i p l e (4 , 5 , 6 ), o rb y r a d i o g ra p h d e n s i t o m e t r y. T h e s e d e n s i t y m e a s u r e m e n t s c o r re l a te c l o s el yw i t h e a c h o t h e r a n d w i t h c h e m i c a l a n a ly s es (7 ). T h e l a t te r s h o w t h a t b o n ef a t f r e e w e ig h t , b o n e a sh , b o n e m a t r i x , a n d t h e c a l c iu m c o n t e n t o f t h e

f e m u r a l l d e c r e a se as a re su l t o f a m m on i um c h l o r i de i nge s ti on* bu t t h er a t i o o f a sh t o m a t r i x a nd t he r e l a t ionsh i p o f f a t f re e we i gh t t o c a l c i umc o n t e n t o f t he bo ne r e m a i n un c ha ng e d ( 4, 5 , 6 ). ( F ig s. 1 a nd 2 ) .Ch r ys t a l l o g r a ph i c a ll y, t he s iz e o f t he a ppa t i t e c r y s ta l s a nd t he pe r c e n t o fc r y st a ll in e a n d a m o r p h o u s f r a c t io n s a re n o t a f f e c t e d b y a m m o n i u mc h l o r i de i nge s t i on ( 5 ).O t h e r o b s e rv a t io n s m a d e i n a n im a l s c h r o n i c a l ly f e d a m m o n i u m c h l o r i d er e ve a l t h a t b l o o d c a l c i u m a n d p h o s p h o r u s a r e n o r m a l ( 4 ). B l o o d s o d i u ma nd po t a s s i um a r e a l so no r m a l ( 4 ), a nd o s t e opo r os i s de ve l ops i n t hep r e s e n c e o f n o r m a l a r te r ia l b l o o d p H ( 4, 8 ). T h e b l o o d c h l o r i d e t e n d s tob e h i g h a n d t h e b l o o d c a r b o n d i o x i d e c o n t e n t s li g ht ly d e p r e s s ed ( 4) .C l e a r ly, t h e o rga n i sm m a ke s a va il a b le s t o r e d ba se bu ff e r, t h e bo nec a r b o n a t e and t h e h y d r o x y a p p a t i t e , t o h e l p m a i n t a i n a c i d b a se n e u t r a l it yi n t he f a c e o f e xc e ss ive i ng e s t i on o f a c i d .

Obse r va t i ons a r e e s se n t ia l ly t h e s a m e w he n m a l e o r f e m a l e r a ts a r es tud ie d (4 , 5 , 6 ). Th e de gree o f os t eopo ros i s th a t is obse rved seem s tod e p e n d o n t h e d o se o f a m m o n i u m c h l o ri d e u s e d a n d th e d u r a t io n o f its

a dm i n i s t r a t i on .L o w c a l c i u m d i e t h a s b e e n s h o w n p r e v i o u s l y t o p r o d u c e o s t e o p o r o s i sb y a p a r a t h y r o i d d e p e n d e n t m e c h a n i s m ( 11 , 1 3). T h e e f f e c t o f a m -m on i um c h l o r i de i s e v i de n t i n a n i m a l s g i ve n a l ow c a l c i um d i e t t o t hesa m e de g r e e a s i n a n im a l s g iv e n a r e gu l a r l a bo r a t o r y d i e t . T h e c om bi n a t i ono f a m m on i um c h l o r i de a nd a l ow c a l c i um d i e t i s a dd i t i ve i n i t s e f f e c t ,c a u s in g a m o r e p r o f o u n d d e g r e e o f o s t e o p o ro s i s th a n e i t h e r a m m o n i u m o ra low ca lc ium d ie t a lon e (4 , 5 ) . (F igs . 1 and 2 ) .

A n o t h e r p o t e n t i a l m e c h a n i s m f o r t h e d e v e l o p m e n t o f o s te o p o r o s is is

t h e w i t h d r a w a l o f e s tr o g e n ic h o r m o n e s ( 1 ). T h e e f f e c t o f a m m o n i u m


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3 0 0 - -

2 5 0 - -

2 0 0 - -

1 5 0 - -

u1 0 C - -

5G

O=REGULAR DIET, Distilledwater y

9 =LChV CALCIU M DIET, 1.5% N H4 CI ~ p ~

@ ~ A A9

y = 0.2146 x +3.463

r= 0.88

- - p= < 0 .0001

10 o I l I I I I I I l Io 600 700 800 900 1000 11 00 1200 13 00 1400 1500

FAT FREE SOLID (mg)

Figure 1. F a t f r ee s o l id w e i g h t a n d c a l c iu m c o n t e n t o f t h e r i g h t f e m u r o f 2 5 0 g m a l er a t s f e d a r e g u l a r o r a l o w c a l c i u m d i e t a n d d i s t i ll e d w a t e r o r 1 .5 % a m m o n i u m c h l o r i d ef o r 3 3 0 d a y s . ( M o d i f i e d f r o m B a r z e l & J o w s e y ( 4 )) .

3 0 0 "

CALCIUMm g

o REGULAR DIET, DISTILLED W ATER'~ REGU LAR DIET, 2% NH4C I9 LOW CALCIUM DIET, DISTILLED W ATER9 LOW CALCIUM DIET, 2% NH4CI

250- o o ~

zO O - 9 ~ 6 o

150- ~ 9 Z~Z~1 . 4 1 4 . 6 X - 4 1 5 . 7~ - 9r 9 0 . 7 8p < 0 . 0 0 0 1

1 0 0 I I I I I I

LSO 0 1.400 I . ,500 1,600D E N S IT Y, g m /c r r r

Figure 2. D e n s i t y a n d c a l c iu m c o n t e n t o f t h e r i g h t f e m u r o f 5 5 0 g m a l e r a ts fe d ar e g u la r o r a l o w c a l c iu m d i e t a n d d i s t il le d w a t e r o r 2 % a m m o n i u m c h l o r i d e fo r 6m o n t h s . ( M o d i f i e d f r o m B a r z e l ( 6 )) -


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chlor ide was co mpa red wi th that of oo ph or ec to my in adul t female rats.Oophorectomized animals , a l lowed a regular d ie t a d l i b . , failed to developany change in bone dens i ty, fa t f ree weight , ash and calc ium content ofthe f emur, excep t when g iven amm oni um ch lo ride. The oopho rec tomi zedanimals were not more sens i t ive to ammonium chlor ide than contro lanimals (6).

R E F E R E N C E S

1. Aitken, J.M., Armstrong, E. & Anderson, J.B.: Osteoporosis in the mature femalerat and the effect of oestroge and/or progesterone replacement therapy in its

prevention. J. E n d o c r. 55, 79--87 (1972)2. Albright, F.A. & Reifenstein, E.C.: T h e P a r a t h y r o i d G l a n d a n d M e t a b o l ic B o n e

D i s ea se : Se l ec t ed S t u d i e s ,Williams and Wilkins, Baltimore, p. 241, 19483. Barzel, U.S.: Acid base balance and bone metabolism: A study in the etiology of

osteoporosis. Clin. Res. 14, 485 (1966)4. Barzel, U.S. & Jowsey, J.: The effect of chronic acid and alkali administra tion on

bone turnover in adult rats. Clin. ScL36, 517-524 (1969)5. Barzel, U.S.: The effect of excessive acid feeding on bone. Calc. Tiss. Res. 4,

94--100 (1969)6. Barzel, U.S.: Studies in osteoporosis: The long term effect of ooph orect omy and

of ammonium chloride ingestion on the bone of mature rats. E n d o c r i n o l o g y96,1304--1306 (1975)7. Colbert, C. & Barzel, U.S.: Radiographic determination o f rat bone mineral loss in

dietary-induced osteopoxosis. In v es t . Rad i o L7, 339--340 (1972)8. Cuisinier-Gleizes, P., Behest, D., George, A. & Thomasset, M.: Thyroparathyroid

glands, bone and acid-base homeostasis. X I t h E u ro p . S y m p . Ca lc . Ti ss ., Ma y25--29, Elsinore, Denmark, Abstract book, p. 70, 1975

9. Delling, G. & Donath, K.: Morphometrische, electronen-mikroskopische undphysikalisch-chemische Untersuchungen u b e r d i e e x p e r i m e n t e l l e O s t e o p o r o s e b e ic h r o n i s c h e r A c i d o s e .Virchows Arch. Path. Anat. Abt. A 358, 321--330 (1973)

10. Goodman, A.D., Lemann, J. Jr. , Lennon, E.J. & Relman, A.S.: Production,excretion, and net balance of fixed acid in patients with renal disease. ]. cl in.In v es t . 44, 495--506 (1965)

11. Harrison, M. & Fraser, R.: Bone structure and metabolism in calcium-deficientrats. J . En d o c r. 21, 197-204 (1960)

12. Jaffe, H.L., Bodansky, A. & Chandler, J.P.: Ammonium chloride decalcification asmodified by calcium intake: relation between generalized osteoporosis and ostitisfibrosa. ]. e x p . M e d .56, 823--834 (1932)

13. Jowsey, J. & Raisz, L.G.: Experimental osteoporosis and parathyro id activity.E n d o c r i n o l o g y82, 384--396 (1968)

14. Lemann, J. Jr. , Lennon, E.J., Goodman, A.D., Litzow, J.R. & Relman, A.S.: Thenet balance of acid in subjects given large loads of acid or alkali. J . c l in . Inves t .44,507--517 (1965)

15. Lemann, J. Jr., Litzow, J.R. & Lennon, E.J.: The effects of chronic acid loads innormal man: Further evidence for the participation of bone mineral in the defenseagainst chronic metabolic acidosis. J. cl in . Inves t .45, 1608--1614 (1966)


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1 6 . L i t z o w, J . R . , L e m a n n , J . J r . , & L e n n o n , E . J .: T h e e f f e c t o f t r e a t m e n t o f a c i d o si so n c a l c i u m b a l a n c e i n p a t i e n t s w i t h c h r o n i c a z o t e m i c re n a l d i se a s e .] . c l in . Inv es t .4 6, 2 8 0 - 2 8 6 ( 19 6 7)

1 7 . R e e d , S .W. & B e c k , N . : A c u t e m e t a b o l i c a c id o s i s o n c a l c i u m m o b i l i z a t i o n f r o mb o n e a n d c a l c iu m e x c r e t i o n , a n d o n p a r a t h y r o i d h o r m o n e a c ti o n s.Cl in . Res . 2 3 ,3 2 8 A ( 1 9 7 5 )

1 8 . R e i d e n b e rg , M . M . , H a a g , B . L ., C h a n n i c k , B . J ., S h u m a n , C . R . & Wi l s o n , T. G . G . :T h e r e s p o n s e o f b o n e t o m e t a b o l i c a c id o s i s i n m a n .M e t a b o l i s m 1 5 , 2 3 6 - 2 4 1( 1 9 6 6 )

1 9 . S c h e n k , M . , R o d s t e i n , M . & B a r z e l , U . S . : F r e q u e n c y a n d r a t e o f p r o g r e s s i o n o fo s t e o p o r o s i s . I s ra e lJ . Me d . Sc i .1 0 , 1 4 7 1 (1 9 7 4 )

2 0 . S m i t h , D . A . , L i n d s a y, R . , B o d d y , K . , E l li o t t, A . & A n d e r s o n , J . : T h e u s e o f t o t a lb o d y i n v ivo n e u t r o n a c t i v a t i o n a n a l y s is in b a l a n c e s t u d ie s i n r o d e n t s .

2 1 . U r is t, M . R ., G u r v e y, M . S . & F a r e e d , D . O . : L o n g t e r m o b s e r v a t i o n s o n a g e d w o m e nw i t h p a t h o l o g i c o s t e o p o r o s i s . I n :O s t e o p o r o s i s , B a r z e l , U . S . ( e d . ) , G r u n e a n dS t r a t t o n , N e w Y o r k , p p . 3 - - 3 7 , 1 9 7 0

Acid Induced Osteoporosis

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