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Chapter 17 Medicinal Chemistry Opportunities in Bone Metabolism and Osteoporosis
Section I V :
E n d o c r i n o l o g y , Immunology and M e t a b o l i c D i s o r d e r s
E d i t o r : W i l l i a m F. Johns, S t e r l i n g - W i n t h r o p Research I n s t i t u t e , Rensselaer, New York 12144 Chapter 17
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M e d i c i n a l Chemistry O p p o r t u n i t i e s i n Bone M e t a b o l i s m and O s t e o p o r o s i s
M a r s h a l l A. Hayward and Thomas J . Caggiano A y e r s t L a b o r a t o r i e s Research I n c . , CN 8000, P r i n c e t o n , NJ 08540 I n t r o d u c t i o n - Bone i s a dynamic t i s s u e which c o n t i n u o u s l y undergoes remodel 1 i n g ( 1 , 2 ) . A p p r o x i m a t e l y 10% o f c o r t i c a l bone ( t h e dense, h i g h l y m i n e r a l i z e d bone w h i c h comprises t h e s h a f t s o f l o n g bones) and 20 t o 40 % o f t h e t r a b e c u l a r bone ( c a n c e l l o u s bone f o u n d i n t h e i n t e r i o r o f v e r t e b r a e and i n t h e m e d u l l a r y space of l o n g bones) i s r e m o d e l l e d each year i n the healthy adult. I n t h i s process m u l t i n u c l e a r o s t e o c l a s t s r e s o r b bone, r e l e a s i n g m i n e r a l and m a t r i x p e p t i d e c o n s t i t u e n t s . T h i s r e s o r p t i o n i s l i n k e d t o a r e b u i l d i n g process i n which o s t e o b l a s t s r e p l a c e eroded bone t i s s u e (see b e l o w ) . Normal Breakdownof Bone
.. .
Bone-absorbmgcells called osteoclasts lit between boneliningcells, above, and dig cavities. below. in the inner sudace of the bone Release0 bone proteins and other substances then I r w r rebuildingprocess
OsteoMasts move into newly created bone m v q . above. and begin rebuildmg bone. hrst by producinga Collagen framework and men mineralizingit with crystalsof cakium and phosphorus In osteopcfosis. less bone IS rebuln than destroyed
New Born
Adolph Brotman; c o p y r i g h t 0 1 9 8 7 by The New York Times Company, R e p r i n t e d by p e r m i s s i o n .
O s t e o p o r o s i s (OP) i s a d e b i l i t a t i n g p r o g r e s s i v e loss o f bone m i n e r a l which u l t i m a t e l y m a n i f e s t s i t s e l f i n e l e v a t e d f r a c t u r e r a t e s , g e n e r a l l y among t h o s e o v e r age 45 ( 3 ) . OP i s most p r e v a l e n t among postmenopausal women, b u t a f f e c t s b o t h sexes. C u r r e n t e s t i m a t e s suggest t h a t 15 t o 20 m i l l i o n persons i n t h e U. S. a r e a f f l i c t e d . More p a t i e n t s w i l l be i d e n t i f i e d as t h e l i f e span i n c r e a s e s . T r a d i t i o n a l l y , modulat i o n o f t h e e n d o c r i n e system has been t h e p r e f e r r e d approach t o t h e management o f OP ( 4 - 7 ) . T h i s r e p o r t w i l l p r o v i d e an o v e r v i e w o f t o p i c s i n p r e c l i n i c a l bone metabolism r e s e a r c h as w e l l as s i g n i f i c a n t new developments i n c l i n i c a l management o f OP. C l i n i c a l Developments - The 1983 NIH consensus c o n f e r e n c e on OP has served t o f o c u s n a t i o n a l a t t e n t i o n on t h e c l i n i c a l management o f OP ( 8 ) . T h i s c o n f e r e n c e recommended t h e use o f postmenopausal e s t r o g e n ANNUAL REPORTS IN MEDICINAL CHEMISTRY-22
Copyright 0 1987 by Academic Press, Inc. All rights of reproduction in any form reserved.
170 Section IV-Endocrinology, Immunology, Metabolic Disorders Johns, Ed. -
replacement t h e r a p y , which has been shown t o d e l a y t h e o n s e t and p r o g r e s s i o n o f OP ( 9 - 1 1 ) . Coupled w i t h adequate d i e t a r y c a l c i u m and e x e r c i s e , t h i s regimen r e p r e s e n t s t h e f i r s t l i n e o f defense a g a i n s t bone demineralization. However, r e p l e n i s h m e n t o f l o s t bone i s n o t a c h i e v e d by t h i s s t r a t e g y . P r o p h y l a c t i c b e n e f i t has a l s o been d e r i v e d f r o m t h e use o f p r o estagens such as n o r e t h i s t e r o n e a l o n e and i n c o m b i n a t i o n w i t h e s t r o g e n s q12-16). P a r a t h y r o i d hormone (PTH) a c u t e l y s t i m u l a t e s bone r e s o r p t i o n v i t r o , as w e l l as a c t i v a t i n g bone r e m o d e l l i n g i n v i v o ( 7 ) . A therap e u t i c r e imen c o n s i s t i n g o f PTH f o l l o w e d b y 1 , 2 5 - d i h y d r o x y v i t a m i n D3 (1,25D3; 17 t r e a t m e n t shows promise as a means t o i n c r e a s e bofie m i n e r a l (17). Progress i n t h e a r e a o f PTH a n t a g o n i s t s i s l i k e l y t o y i e l d i n s i g h t i n t o t h i s approach ( 1 8 ) . V i t a m i n D m e t a b o l i t e s such as 1 may p l a y a d i r e c t , p i v o t a l r o l e i n t h e development o f OP ( 1 9 , 2 0 ) . These m e t a b o l i t e s r e g u l a t e t h e f u n c t i o n o f d i f f e r e n t i a t e d human o s t e o b l a s t s , monocytes and lymphocytes, s e r v i n g t o m e d i a t e bone m e t a b o l i s m a t s e v e r a l l e v e l s (21,22). C a l c i t o n i n (CT), known t o decrease t h e bone r e s o r p t i o n process and have d i r e c t i n h i b i t o r y e f f e c t s on o s t e o c l a s t s i n v i t r o ( 2 3 ) , has shown e f f i c a c y i n one and two y e a r t r i a l s (24,25). I n m o n to d i r e c t e f f e c t s on bone r e s o r p t i o n , CT may s e r v e t o i n c r e a s e bone format i o n by a l t e r i n g v i t a m i n D3 m e t a b o l i s m ( 2 6 ) . S i g n i f i c a n t drawbacks o f CT t h e r a p y a r e t h e r e q u i r e m e n t f o r p a r e n t e r a l a d m i n i s t r a t i o n and p o t e n t i a l a n t i g e n i c i t y o f t h e p e p t i d e ; however, salmon CT has been s u c c e s s f u l l y d e l i v e r e d i n t r a n a s a l l y . Human CT i s a v a i l a b l e (27,28). CT l e v e l s a r e u n a f f e c t e d by e s t r o g e n t h e r a p y and i t i s t h o u h t t h a t p o s t menopausal OP i s n o t m e d i a t e d by a p r i m a r y CT d e f i c i e n c y ?29,30). ~
I n a two-year s t u d y , d i e t a r y c a l c i u m s u p p l e m e n t a t i o n a l o n e was i n s u f f i c i e n t t o guard a g a i n s t t h e development of postmenopausal GP (31). Adequacy o f c a l c i u m i n t a k e can, however, s e r v e t o r e t u r n an i n d i v i d u a l t o p o s i t i v e calcium balance (32). The i m p a c t o f c a l c i u m d e f i c i e n c y on p a t i e n t response t o t h e r a p y i s an i m p o r t a n t concern i n t h e d e s i g n of c l i n i c a l s t u d i e s ( 3 3 ) . Calcium supplements have, however, been shown t o i n c r e a s e t h e c a l c i u m b a l a n c e o f a d o l e s c e n t g i r l s o v e r a two week span, s u g g e s t i n g t h a t adolescence i s a c r i t i c a l p e r i o d f o r skeletal calcium accretion (34). Nevertheless, t h e n o t i o n t h a t i n c r e a s i n g s k e l e t a l mass p r i o r t o menopause w i l l p r o t e c t against o s t e o p o r o s i s has been c a l l e d i n t o q u e s t i o n ( 3 5 ) . F a m i l y h i s t o r y and s k e l e t a l a t t r i b u t e s a r e i m p r e c i s e , b u t a r e o f t e n as p r e d i c t i v e as more s o p h i s t i c a t e d t e c h n i q u e s i n p r o v i d i n g a c c u r a t e OP r i s k assessment (36). W h i l e d e t e r m i n a t i o n s o f bone m i n e r a l c o n t e n t i n l o n g i t u d i n a l s t u d i e s a r e u s e f u l , t h e i n f o r m a t i o n may come t o o l a t e t o benefit the individual patient. Assays (e.g., serum o s t e o c a l c i n measurements) have appeared, o n l y t o be deemed more a p p r o p r i a t e as i n d i c a t o r s of t h e s t a t u s o f bone t u r n o v e r ( 3 7 ) . Several assays c u r r e n t l y r e c e i v i n g a t t e n t i o n a r e a l u t e i n i z i n g hormone r e l e a s i n g hormone (LHRH) i n d u c e d menopause, a l k a l i n e phosphatase isozyme measurements, serum a c i d phosphatase a c t i v i t y , serum v i t a m i n K l e v e l s , and T lymphoc y t e s u b s e t a n a l y s e s (38-42).
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P r e c l i n i c a l Research U n d e r s t a n d i n g t h e mechanism by which m i n e r a l homeostasis and mechanical f u n c t i o n a r e m a i n t a i n e d i s c r i t i c a l t o t h e development o f improved t h e r a p y f o r OP ( 4 3 ) . The o r i g i n , development and d i f f e r e n t i a t i o n of bone c e l l s i s an i n t e n s e l y i n v e s t i g a t e d t o p i c (44,451. I t has been proposed t h a t o s t e o b l a s t s a r e key r e g u l a t o r y c e l l s i n bone. O b s e r v a t i o n s c o n c e r n i n g hormone e f f e c t s s u p p o r t t h i s n o t i o n
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(46-48). C y t o k i n e s produced b y macrophages o r c e l l s o f t h e immune system may p r o v i d e a d d i t i o n a l l e v e l s of c o n t r o l on bone r e m o d e l i n g (49-56). As more i s l e a r n e d a b o u t t h e development and d i f f e r e n t i a t i o n of o s t e o c l a s t s and t h e r o l e o f c a l c i t r o p i c hormones on bone c e l l a c t i v i t y , a d d i t i o n a l approaches t o t h e m o d u l a t i o n o f m i n e r a l homeostasis w i l l be r e a l i z e d . I n t h i s r e g a r d , bone m a t r i x i t s e l f i s a r i c h s o u r c e of t h e s e a c t i v i t i e s and many p e p t i d e f a c t o r s i s o l a t e d f r o m bone have been r e p o r t e d t o modulate bone metabol ism (57-59). Animal Models - W h i l e t h e r e a r e many a c c e p t e d i n v i t r o assays f o r bone r e s o r p t i o n and f o r m a t i o n , p r e c l i n i c a l i n v i v o models o f bone m e t a b o l i s m a r e s t i l l b e i n g e s t a b l i s h e d (60,611. S t u d i e s i n non-human p r i m a t e s i n d i c a t e t h a t o v a r i e c t o m y produces a n e t decrease i n b o t h i l i a c and v e r t e b r a l t r a b e c u l a r bone (baboons and cynomolgus monkeys respectively) (62,63). Canines s u b j e c t e d t o o v a r i e c t o m y showed a l o w e r bone m i n e r a l content i n the i l i a c c r e s t than controls, w i t h the d e f i c i t ascribed t o depressed bone f o r m a t i o n , a r e s u l t o f decreased o s t e o b l a s t a c t i v i t y ( 6 4 ) . A l i m i t a t i o n o f t h e s e models i s t h e t i m e (months) r e q u i r e d f o r t h e development o f OP; t h u s , a s i g n i f i c a n t c h a l l e n g e t o i n v e s t i g a t o r s i n t h e f i e l d i s t o d e v e l o p s h o r t e r - t e r m models o f OP. H i s t o l o g i c changes i n r o d e n t s i n d u c e d by tenotomy o r d e n e r v a t i o n o c c u r w i t h i n days, whereas o v a r i e c t o m y i n d u c e d bone loss o c c u r s o v e r a span of weeks (65-67). Such models have t h e p o t e n t i a l t o b r i d g e t h e gap between i n v i t r o and extended i n v i v o s t u d i e s i n l a r g e r s p e c i e s . I m p l a n t s o f bone m a t r i x can be u t i l i z e d t o s t u d y endochondral o s s i f i c a t i o n (68,69). Loss o f bone m i n e r a l i s a c c e l e r a t e d i n some s t r a i n s of m i c e ( w i t h o u t s u r g i c a l o r m e t a b o l i c c h a l l e n g e ) , which may p r o v i d e a model f o r s e n i l e OP ( 7 0 ) . C o r r e l a t i o n o f t h e s e models w i t h r e g a r d t o human d i s e a s e r e p r e s e n t s a major challenge. Pharmacologic e f f e c t o r s o f bone m e t a b o l i s m - A l a r g e number of s t r u c t u r a l l y d i v e r s e compounds have been r e p o r t e d t o m e d i a t e bone metabolism. I t i s i m p o r t a n t t o n o t e t h e dose l e v e l used i n a l l o f t h e cases c i t e d below because t h e l e v e l r e q u i r e d t o e l i c i t a response i s o f t e n w e l l above o r w e l l below t h o s e r e q u i r e d t o e l i c i t o t h e r t y p e s of pharmacologic a c t i v i t y . E n d o c r i n e Agents - E n d o c r i n e m e d i a t o r s o f bone m e t a b o l i s m a r e g e n e r a l l y sex o r c a l c i t r o p i c hormcnes ( 7 1 ) . However, r e c e n t r e p o r t s o f bone s p a r i n g e f f e c t s o f c o r t i c o s t e r o i d s and t h e modest t o v e r y l o w r i s k o f OP i n p a t i e n t s on l o w dose p r e d n i s o l o n e f o r r h e u m a t o i d a r t h r i t i s a r e encouraging (72-74). I n t h e case o f a n a b o l i c s t e r o i d s t h e r e s u l t s a r e mixed. Dehydroepiandrosterone f a i l e d t o a m e l i o r a t e o v a r i e c t o m y i n d u c e d OP i n r o d e n t s ( 7 5 ) y e t s t a n a z o l o l ( 2 ) caused a n e t i n c r e a s e i n t o t a l body c a l c i u m i n a 29 month s t u d y i n postmenopausal OP women ( 7 6 ) . Bone
172 S e c t i o n IV-Endocrinology, Immunology, M e t a b o l i c D i s o r d e r s Johns, Ed. f o r m a t i o n r a t e s were m a r g i n a l l y i n c r e a s e d i n t h e s t a n a z o l o l t r e a t e d group r e l a t i v e t o b a s e l i n e measurements, b u t b o t h t e s t and c o n t r o l groups were t r e a t e d w i t h c a l c i u m , and showed a s l i g h t i n c r e a s e r e l a t i v e an a n a l o g o f improved t h e t o baseline. Dihydrotachysterol a b i l i t y o f marrow s t r o m a l c e l l s f r o m o v a r i e c t o m i z e d r a t s t o p r o l i f e r a t e i n v i t r o , as w e l l as i n c r e a s i n g o s t e o g e n i c parameters i n i m p l a n t g r a f t s (7t).In t h e same model system, e s t r o g e n i n c r e a s e d t h e i n v i t r o c o l o n y f o r m i n g a b i l i t y o f marrow s t r o m a l c e l l s , b u t d i d n o t i n c r e a s e t h e & v i v o osteogenic p r o p e r t i e s o f these c e l l s (78).
(z),
1,
Bisphosphonates - The bisphosphonates ( 4 ) , c a r b o n analogs o f pyrophosphate, have been e x t e n s i v e l y e x p l o r e d (79,80). They g e n e r a l l y i n h i b i t b o t h t h e c r y s t a l l i z a t i o n and d i s s o l u t i o n o f c a l c i u m phosphate i n v i t r o . Etidronate (5) i s the strongest i n h i b i t o r s t u d i e d . When t h e s u b s t i t u e n t s a r e h a l o o x 6 gens (6,7)one sees s t r o n g i n h i b i t i o n of bone r e s o r p t i o n . 7 i n h i b i t s bone r e s o r p .=;+Lo 4 I I tion and remodeTing w i t h o u t i n h i b i t i n g HO Y O H m i n e r a l i z a t i o n (81, 8 2 ) . Bisphosphonates X Y a r e r e p o r t e d t o i n h i b i t macrophage m i g r a 5 OH CH, t i o n ( 8 3 ) . S t u d i e s on t h e a b i l i t y o f 6 and 8 t o i n h i b i t the formation o f resorp6 CI CI 7 F F t i o n Tacunae and PTH i n d u c e d s e c r e t i o n o f 8 OH (cH,),NH, lysosomal h y d r o l a s e suggest t h e s i t e o f a c t i o n t o be t h e o s t e o c l a s t as opposed t o t h e o s t e o b l a s t (84). 8 i s a l s o useful i n t r e a t i n g j u v e n i l e OP, a d i s e a s e i n which t h e p r i m a r y d e f e c t i s u n a t t e n u a t e d a c t i v i t y o f metaphyseal o s t e o c l a s t s (85). F l u o r i d e - A u s e f u l t h e r a p e u t i c a g e n t would i n c r e a s e bone mass as w e l l as decrease t h e f r a c t u r e r a t e . F l u o r i d e may r e p r e s e n t such an approach t o t h e c l i n i c a l management o f OP. I n t h e spayed b e a g l e dog, h i s t o l o g i c e v a l u a t i o n o f bone showed a number o f f l u o r i d e e f f e c t s ( 8 6 ) . These i n c l u d e a c t i v a t i o n o f bone t u r n o v e r , and a l t e r a t i o n s o f t h e d i f f e r e n t i a t i o n and a c t i v i t y of b o t h o s t e o b l a s t s and o s t e o c l a s t s . Increased o s t e o b l a s t i c a c t i v i t y i n v i t r o as w e l l as bone f o r m a t i o n i n v i v o a r e r e s u l t s of f l u o r i d e exposure. However, f l u o r i d e dose and t h e a v a i l a b i l i t y of m i n e r a l c o n s t i t u e n t s must be p r o p e r l y m a i n t a i n e d t o a v o i d t h e development of an o s t e o s c l e r o t i c s k e l e t o n ( 8 7 ) . I n one s t u d y , o n l y t h o s e p a t i e n t s d e v e l o p i n g s k e l e t a l f l u o r o s i s showed a decrease i n vertebral fracture r a t e (88). F l u o r i d e may a l t e r t r a c e m i n e r a l m e t a b o l i s m (Zn, Mn) w i t h i n bone, e f f e c t s t h a t may have l o n g t e r m consequences (89,90). Some untoward s i d e e f f e c t s o f sodium f l u o r i d e t h e r a p y may be a l l e v i a t e d b y t h e a d m i n i s t r a t i o n of monofluorophosphate (MFP), w h i c h has an a c t i v i t y p r o f i l e s i m i l a r t o t h a t o f sodium f l u o r i d e i n v i t r o . Workers have demonstrated t h e a b i l i t y o f a l k a l i n e phosphatase i n c h i c k s k e l e t a l t i s s u e t o h y d r o l y z e MFP, t h u s p r o v i d i n g f r e e f l u o r i d e a t s k e l e t a l s i t e s (91). Enzyme I n h i b i t i o n - The i n v o l v e m e n t o f t h e enzyme c a r b o n i c anhydrase 1EC4.2.1.11 i n t h e bone r e s o r p t i o n process has been extended b y o b s e r v a t i o n s s u g g e s t i n g t h a t l i m b d i s u s e a t r o p h y may be a l l e v i a t e d by a d m i n i s t r a t i o n of c a r b o n i c anhydrase i n h i b i t o r s ( 9 2 ) . An i n s u f f i c i e n c y i n c a r b o n i c anhydrase was i d e n t i f i e d as t h e p r i m a r y d e f e c t i n o s t e o p e t r o s i s , a d i s e a s e c h a r a c t e r i z e d b y i n s u f f i c i e n t bone r e s o r p t i o n ( 9 3 ) . Carbonic anhydrase has been d e t e c t e d i n t h e o s t e o c l a s t i n p h y s i o l o g i c a l l y important Quantities (94). The enzyme i s a s s o c i a t e d w i t h t h e a c t i v e r e s o r b i n g zone of t h e o s t e o c l a s t a f t e r exposure t o PTH, and
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becomes d i s p e r s e d t h r o u g h o u t t h e c e l l a f t e r exposure t o CT ( 9 5 ) . An i n c r e a s e i n t h e a c i d i t y of o s t e o c l a s t s i s s t i m u l a t . e d by PTH, a process p a r t i a l l y i n h i b i t e d by c a r b o n i c anhydrase i n h i b i t o r s ( 9 6 ) , such as ( 9 ) . 9 i n h i b i t s both a c e t a z o l amide S p r o s t a g l a n d i n E2 and T,25D3 stimulated CH3C0NH% k s 0 z N H 2 bone r e s o r p t i o n (97,981. It i s noteworthy 9 N-N t h a t improvement o f c a r b o n i c anhydrase i n h i b i t i o n i s not necessarily well correl a t e d w i t h a s i m i l a r improvement i n bone r e s o r p t i o n i n h i b i t i o n ( 9 9 ) . T h i a z i d e d i u r e t i c s , which a r e r e c o g n i z e d f o r c a l c i u m r e t e n t i o n p r o p e r t i e s , a r e a l s o c a r b o n i c anhydrase i n h i b i t o r s ; t h e s e compounds have r e c e i v e d some a t t e n t i o n as p o t e n t i a l a n t i o s t e o p o r o t i c s (100,103). Other c o m p l i c a t i o n s of t h i a z i d e t h e r a p y may a r i s e , however, such as reduced i n t e s t i n a l c a l c i u m a b s o r p t i o n (104,105). E x a m i n a t i o n o f t h e mechanism by which o s t e o c l a s t s g e n e r a t e an a c i d i c environment has demonstrated t h e p r e sence o f an ATPase i n t h e membrane o f t h e s e c e l l s (106,107). T h i s enzymatic a c t i v i t y appears t o be f u n c t i o n a l l y and t e m p o r a l l y a s s o c i a t e d w i t h t h e r e s o r p t i o n process (108). Omeprazole a pharmacologic i n h i b i t o r o f K+/H+ ATPase known t o i n h i b i t g a s t r i c a c i d s e c r e t i o n , i n h i b i t s bone r e s o r p t i o n i n v i t r o ( 1 0 9 ) .
(g),
Collagenase i s s y n t h e s i z e d and s e c r e t e d as p r o c o l l a g e n a s e by o s t e o b l a s t s i n response to resorption stimulators. Collagenase i n h i b i t o r s a r e s y n t h e s i z e d and s e c r e t e d as w e l l (110,111). I n an e l e g a n t s e r i e s of e x p e r i m e n t s , t h e a b i l i t y o f i s o l a t e d o s t e o c l a s t s t o degrade bone s u b s t r a t e was markedly enhanced by p r e - i n c u b a t i o n o f bones w i t h c a l v a r i a l c e l l s o r w i t h exogenous c o l l a g e n a s e ( 1 1 2 ) . Calvarial c e l l s a l o n e a r e a b l e t o degrade o s t e o i d , b u t n o t m i n e r a l i z e d t i s s u e . Taken t o g e t h e r , t h e s e o b s e r v a t i o n s s u p p o r t t h e n o t i o n t h a t o s t e o b l a s t i c c e l l s may p h y s i c a l l y p r e d i s p o s e bone m i n e r a l t o f u r t h e r d i g e s t i o n by o s t e o c l a s t s (see a1 s o t h e accompanying c h a p t e r on o s t e o a r t h r i t i s )
.
P r o s t a g l a n d i n E2 i s a s t i m u l a t o r o f bone r e s o r p t i o n and t h u s may c o n t r i b u t e t o bone l o s s , p a r t i c u l a r l y when a s s o c i a t e d wit,h COOH i n f l a m m a t i o n (e.g., i n periodontal d i s ease; 113,114). Flurbiprofen has 11 been shown t o be a p o t e n t i n h i b i t o r o f a l v e o l a r bone loss i n beagles ( 1 1 5 ) . C l i n i c a l s t u d i e s a r e i n p r o g r e s s . H3
(E),
- T h i o p h e n e - 2 - c a r b o x y l i c a c i d (TCA) was Thiophene c a r b o x y l i c a c i d s o r i g i n a l l y d e s c r i b e d as a hypoglycemic antilipolytic agent with hypocalcemic and hypophosphatemic a c t i v i t y ( 1 1 6 ) . Subsequent s t u d i e s showed t h a t TCA i n h i b i t e d r e s o r p t i o n o f n e o n a t a l mouse c a l v a r i a i n v i t r o (117). BL5583 ( 1 2 ) and BL5593 ( 1 3 ) have been shown t o be a c t i v e a g a i n s t h e p a r i n - a c c e l e r a t a OP ( 1 1 8 ) . Recent work has extended t h i s c l a s s t o i n c l u d e aza analogs, i n d o l e - 2 - c a r b o x y l i c a c i d and c a r b a z o l e - 1 - c a r b o x y l i c The most a c i d ( 1 4 ) , as i n h i b i t o r s o f PTH s t i m u l a t e d bone r e s o r p t i o n . 1 2 ) has been shown t o t r a n s i e n t l y i n h i b i t potent-compound s t u d i e d (c e l l u l a r Ca++ uptake ( 1 1 9 ) , y e t n o t a l t e r i n t r a c e l l u l a r CAMP ( 1 2 0 ) . I n t e r e s t i n g l y , i n a s e p a r a t e s t u d y , t h e Ca++ channel b l o c k e r d i l t i a z e m was shown t o be i n e f f e c t i v e as an i n h i b i t o r o f u n s t i m u l a t e d bone r e s o r p t i o n , y e t was e f f e c t i v e as an i n h i b i t o r o f 1,25D3 s t i m u l a t e d bone r e s o r p t i o n ( a s j u d g e d by 45Ca and h y d r o x y p r o l i n e r e l e a s e ; 1 2 1 ) .
(5)
174
S e c t i o n IV-Endocrinology,
Immunology, M e t a b o l i c D i s o r d e r s
J o h n s , Ed. OCH,
~
c
o
o
H
12
13 14
X
S NH
R
2-COOH 1-COOH
15
-
_Lysosomal Enzyme Release I n h i b i t o r s (LERI) LERI ( c h l o r o q u i n e , hydroxys t i l b a m i d i n e , dapsone, and l e v a m i s o l e (L-16) have beer: demonstrated t o inhibit bone r e s o r p t i o n i n v i t r o (In). U n l i k e i t s a n t h e l m i n t i c a c t i v i t y , levamisole's a b i l i t y t o i n h i b i t resorption i s not stereospecific (123). Dexamisole (D-16) and b r o m o t e t r a m i s G l e have similar activity. Levamisole and i t s congeners inhibit lactate p r o d u c t i o n and a1 k a l i n e phosphatase (124,125). B o t h enantiomers of a r e a p p r o x i m a t e l y 10 f o l d more a c t i v e t h a n l e v a m i s o l e as i n h i b i t o r s o f 45Ca r e l e a s e f r o m c u l t u r e d e x p l a n t s . These compounds may a c t d i r e c t l y on o s t e o c l a s t s t o i n h i b i t r e s o r p t i o n , r a t h e r t h a n by a r e c e p t o r m e d i a t e d event. P h e n o t h i a z i n e d e r i v a t i v e s have a l s o been shown t o i n h i b i t a l k a l i n e phosphatase i n o s t e o b l a s t i c c e l l s (126). For example, promethazine n o t o n l y i n h i b i t s r e s o r p t i o n (127) b u t leads t o r e t e n t i o n o f bone mass i n a g i n g m i c e ( 1 2 8 ) . Promethazine e f f e c t s have been a t t r i b u t e d t o d i r e c t i n h i b i t i o n o f macrophage a c t i v i t y (e.g., p r o s t a g l a n d i n r e l e a s e and p h a g o c y t o s i s ) .
(17)
(17)
(18)
16 17
R=H
R = Br
I n c i d e n t a l R e p o r t s - The compounds r e p o r t e d h e r e have been t h e s u b j e c t s i n g l e papers on a c t i v i t y i n bone metabolism. F o r t h e most p a r t , t h e mode o f a c t i o n i s n o t w e l l understood. of
cAMP p h o s p h o d i e s t e r a s e has been i d e n t i f i e d i n bone t i s s u e (129). S e v e r a l r e p o r t s have appeared on t h e e f f e c t o f PDE i n h i b i t o r s on bone m e t a b o l i c processes. The c a r d i o t o n i c agent m i l r i n o n e (19) has been demonstrated t o e l i c i t an i n c r e a s e i n bone r e s o r p t i o n i n v x r o ( 1 3 0 ) , i n c o n t r a s t t o amrinone an i n h i b i t o r o f r e s o r p t i o n . P e n t o x i f y l l i n e (21), a methyl xanthine d e r i v a t i v e , i n c r e a s e d Ca++ u p t a k e and cAMP The l e v e l s r e q u i r e d p r o d u c t i o n i n r o d e n t o s t e o b l a s t - l i k e c e l l s (132). f o r Ca++ u p t a k e were w e l l below t h o s e needed t o i n c r e a s e cAMP p r o d u c t i o n ( 1 3 3 ) . T h i s was c o n s t r u e d t o suggest a mechanism n o t dependent on PDE inhibition. BL3459 ( 2 2 ) and BL4160 ( 2 3 ) , were report.ed t o i n h i b i t h e p a r i n i n d u c e d OP i n f i c e ( 1 3 4 ) . I p r i n a v o n e (24) i s r e p o r t e d t o augment t h e a b i l i t y o f e s t r o g e n t o e l i c i t CT s e c r e t i o n i n t h e response t o a serum c a l c i u m c h a l l e n g e (135). I n r a t s w i t h g l u c o c o r t i c o i d i n d u c e d OP, 24 suppressed r e s o r p t i o n i n t h e rnetaphyses and p o s s i b l y i n h i b i t e d bone G s s i n t h e diaphyses ( 1 3 6 ) . G a l l i u m n i t r a t e has shown u t i l i t y i n t h e a m e l i o r a t i o n o f h y p e r c a l c e m i a a s s o c i a t e d w i t h m a l i g n a n c y (137,138).
(g),
Chap. 17
Bone M e t a b o l i s m and O s t e o p o r o s i s
H
19 20
X R CN CH, NH, H
Hayward, C a g g i a n o
175
24
RQ o -J-
Summary - I n t h e 5 y e a r s s i n c e t h e l a s t r e v ew o f bone rnetabo ism appeared i n t h i s s e r i e s , o u r knowledge o f b a s i c bone m e t a b o l i s m has g r e a t l y increased (4). P r a c t i c a l i n v i t r o and n v i v o models . a .r e - now a v a i l a b l e t o s e r v e as a b a s i s f o r t h e s t u d y o f sy t h e t i c m e d i a t o r s o f bone metabolism. Thus, t h e development of n o v e l - t h e r a p e u t i c approaches t o t h e c l i n i c a l management o f d i s e a s e represents a significant opportunity i n medicinal chemistry. REFER E N c E s
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
11. 12. 13.
14. 15. 16. 17. 18. 19.
20.
21. 22. 23. 24. 25. 26.
H.M. F r o s t i n "Bone and M i n e r a l Research, Annual 3," W.A. Peck, Ed., E l s e v i e r , Amsterdam, 1985, p. 49. Peck, Ed., Excerpta P.J. Meunier i n "Bone and M i n e r a l Research, Annual 1," W.A. Medica, E l s e v i e r , Amsterdam, 1983, p. 191. B.J. C u l l i t o n , Science, 235, 833 ( 1 9 8 7 ) . F.R. S i n g e r i n " A n n u a r R e p o r t s i n M e d i c i n a l C h e m i s t r y " , H.-J. Hess, Ed., Academic Press, New York, 1981, V o l . 17, C h a p t e r 26. H.F. Gruber, N. B r a u t h a r , Nephron, 38, 76 ( 1 9 8 4 ) . A.D. Woolf, A.S.J. Dixon, Drugs, 28,-565 (1984). Med., 309, 29 ( 1 9 8 3 ) . L.G. R a i s z , B.E. Kream, N. Engl . W.A. Peck, Chairman, J.A.M.A., 252, 799 (lm). R . L i n d s a y , O.M. H a r t , and D . M . T a r k , O b s t e t . Gynecol., 63, 759 ( 1 9 8 4 ) . B. E t t i n g e r , H.K. Genant, and C . E . Cann, Ann. I n t e r n . Med, 319 ( 1 9 8 5 ) . F.W. L a f f e r t y , 0.0. Helmuth, M a t u r i t a s , 7, 147 ( 1 9 8 5 ) . C. C h r i s t i a n s e n , A c t a Pharmacol. T o x i c o l T , 59, Sup. V I I , 305 ( 1 9 8 6 ) . P.L. S e l b y , M. Peacock, S.A. B a r k w o r t h , W.BrBrown, and G.A. Taylor, C l i n . Sci., 69, 265 ( 1985). C h r i s t i a n s e n , B.J. R i i s , L . N i l a s , and P. Rodbro, L a n c e t , 1. 800 ( 1 9 8 5 ) . P.L. Selby, M. Peacock, L a n c e t , 2, 1194 ( 1 9 8 5 ) . H . I . A b d a l l a , D.M. H a r t , R . L i n d s a y , I . Leggate, and A. Hooke, O b s t e t . Gynecol., 66, 789 ( 1 9 8 5 ) . K M . S l o v i k , M.A. D a l y , S.H. O o p p e l t , J.T. P o t t s , D . I . R o s e n t h a l , and R.M. Neer, J . Bone Min. Res. S u p p l . 1, A b s t r a c t No. 169, ( 1 9 8 6 ) . M. R o s e n b l a t t , N. E n g l . J. Med., 315, 1004 ( 1 9 8 6 ) . K.S. T s a i , H. Heath 111, R. Kumar, and B.L. Riggs, J. C l i n . I n v e s t . , 1668 (1984). E.S. O r w o l l , O.E. M e i e r , J. C l i n . E n d o c r i n o l . Met., 63, 1262 ( 1 9 8 6 ) . H. S k j o d t . J.A. G a l l a g h e r , J.N. B e r e s f o r d , M. E u c h , J.W. Poser, and R.G.G. R u s s e l l , J. E n d o c r i n o l . , 391 (1985). S. Manolagos, C . Tsoukas, D. P r o u v e d i n i , and B. L a n d g r a f f , J. Bone Min. Res., Suool. 1. A b s t r a c t No. 12. ( 1 9 8 6 ) . T.J: Chambers, J.C. Chambers, J . ' Symonds, and J.A. Darby, J . C l i n . E n d o c r i n o l . Met., 63. 1080 ( 1 9 8 6 ) . G.F. &zuoli, M. P a s s e r i , C. Gennari, S. M i n i s o l a , R . A n t o n e l l i , C . V a l t o r t a , E. .Palunnneri, G.F; C e r v e l l i n , S. G o n n e l l i , and G. F r a n c i n i , C a l c i f . T i s s u e I n t . , 21 3 (1986). H.E. Gruber, J.L. I v e y , D.J. B a y l i n k , M. Matthews, W.N. N e l p , K. Sisorn, and C.H. Chesnut 111, M e t a b o l i s m , 33, 295 ( 1 9 8 4 ) . P. Jaeger. W. Jones, T.L. C l e r n z s , and J.P. H a y s l e t t , J. C l i n . I n v e s t . , 456 (1986).
102,
1,
73,
2,
1,
2,
176 -
S e c t i o n IV-Endocrinology
,
Immunology, M e t a b o l i c D i s o r d e r s
J o h n s , Ed.
T. B u c l i n , J.P. Randin, A.F. Jacquet, M. A z a r i a , M. A t t i n g e r , F. Gomez, P. B u r c k h a r d t , J. Bone Min. Res. 1, Suppl 1, A b s t r a c t No. 347 ( 1 9 8 6 ) . Endicott, M.I. 28. J.C. Stevenson, J.M. Banks, I. M c I n t y r e , R. Hesp, M. Padwick, J.A. Whitehead, J. Bone Min. Res. 1, Suppl. 1, A b s t r a c t No. 277 ( 1 9 8 6 ) . S u p p l . 1, A b s t r a c t H u r l e y , R , D , T i e g s , ana H . Heath 111, J. Bone Min. Res., 29. D.L. No. 447, ( 1 9 8 6 ) . 30. J. Leggate, E. F a r i s h , C.D. F l e t c h e r , W. M c I n t o s h , D.M. H a r t , and J.M. Sommerville, C1 i n . E n d o c r i n o l , 20, 85 ( 1 9 8 4 ) . 31. B. R i i s , K.Thomsen,T. C h r i s t i a n s e n , N. E n g l . J. Med., 316, 173 ( 1 9 8 7 ) . R.P. Heaney, J.C. G a l l a g h e r , C.C. Johnston, R. N e e C A . M. P a r f i t t , B. C h i r , and 32. G.D. Whedon, Am. J. C l i n . N u t r . , 986 (1982). Chesnut 111, and E.J. Teubner, C a l c i f . Tissue 33. J.M. B u r n e l l , D.J. B a y l i n k , C.H. I n t . , 38, 187 ( 1 9 8 6 ) . M a n o v i c , 0. Fontana, C. Tominac, J. Lehmann, and C. Chestnut, J. Bone Min. Res. 34. V. 1, Suppl. 1, A b s t r a c t No. 168 ( 1 9 8 6 ) . 319 ( 1 9 8 6 ) . 35. G.S. Gordan, C. Vaughan, J. N u t r . , 36. F.M. H a l l , M.A. D a v i s , and D.T. Baran, N. E n g l . J . Med., 316, 212 ( 1 9 8 7 ) . M.C. Chapuy, and P.J. Meunier, 37. J.P. Brown. P.D. Delmas, L. M a l a v a l , C. Edouard, L a n c e t , 1, 1094 ( 1 9 8 4 ) . 255, 1600 ( 1 9 8 6 ) . 38. R. Abbasi, G.D. Hodgen, J.A.M.A., C o l l i n s , A. Rim, K. Bowman, and D . V . F o l e y , Am. J . O b s t e t . Gynecol., 39. D . P . (31, ( 1 9 8 4 ) . Stepan, J. P o s p i c h a l , J . P r e s l , and V . Pacovsky, in "Osteoporosis-I: 40. J.J. on Osteoporosis, Proceedings of the Copenhagen International Symposium C . C h r i s t i a n s e n Ed., G l o s t r u p H o s p i t a l , G l o s t r u p , Denmark, 139 ( 1 9 8 4 ) . Sambrook, R.A. 41. J.P. H a r t , M.J. Shearer, L . Klenerman, A. C a t t e r a l l , J. Reeve, P.N. Dodds, L. B i t e n s k y and J. Chayen, J. C l i n . Endocrin.Met., 60, 1268 ( 1 9 8 5 ) . F u j i t a , T. M a t s u i , Y . Nakao, S. Watanabe, M i n e r . E l e c t r o l y t e Metab., 375 42. T. (1984). 43. A.M. P a r f i t t , C a l c i f . T i s s u e I n t . , 2 , S123 ( 1 9 8 4 ) . Baylink, Miner. 44. H . E . Gruber, J.L. I v e y , E . R . Thompson, C.H. Chesnut 111, and D.J. E l e c t r o l y t e Metab., 12, 246 ( 1 9 8 6 ) . 45. P.J. N i j r i e i d e , E . H . B u r g e r , a n d J.H.M. Feyeii, P h y s i o l . Rev., 66, 855, ( 1 9 8 6 ) . G.A. Rodan, T.J. M a r t i n , C a l c i f . T i s s u e I n t . , 33, 349 ( 1 9 8 1 ) . 46. 47. G.L. Wong, J. B i o l . Chem., 259, 4019 ( 1 9 8 4 ) . B.M. Thomson, J. S a k l a t v a l a x n d T.J. Chambers, J . Exp. Med., 104 ( 1 9 8 6 ) . 48. i n "Developments i n C e l l B i o l o g y , 1. S e c r e t o r y Processes", R.T. Dean, P. 49. G. Vaes, S t a h l , Eds, B u t t e r w o r t h s , London, 1985, Chapter 6. 50. M. H o r o w i t z , A. V i g n e r y , R . K . Gershon, and R . Earon, P r o c . N a t l . Acad. S c i . USA, 81, 2181 ( 1 9 8 4 ) . 3544 ( 1 9 8 6 ) . 51. N. Takahashi, G.R. Mundy, and G . D . Roodrnan, J. Immunol 52. K.J. I b b o t s o n , G.D. Roodrnan, L.M. McManus, and G.R. Mundy, J . C e l l B i o l . , 99, 471 (1984). 363 53. R. Baron, L . N e f f , P. T.Van, J.R. N e f u s s i , and A. V i g n e r y , Am. J. P a t h o l . , (1986). Kahn, E . C . Crouch, J . J . J e f f r e y , and S.L. Teitelbaurn, J . C e l l B l a i r , A.J. 54. H.C. Biol., 1164 ( 1 9 8 6 ) . 55. T.J. Chambers, P.M.J. McSheehy, B . M . Thomson, and K . F u l l e r , E n d o c r i n o l o g y , 234 (1985). 56. R.L. J i l k a , Bone, 7, 29 ( 1 9 8 6 ) . 57. S. Mohan, T. L i n k h a r t , J . F a r l e y , and D. B a y l i n k , C a l c i f . T i s s u e I n t . , 2 , 5139 (1984). 58. E . C a n a l i s , C l i n . Orthop., 193, 246 ( 1 9 8 5 ) . I a f r a t i , S.E. Doleman, and M. K l a q s b r u n , J . 59. P.V. Hauschka, A.E. M a v r a k o x M.D. B i o l . Chem., 261, 12665 ( 1 9 8 5 ) . 60. W.A. Soskolne, Z . Schwartz, and A. Ornoy, Bone, 7 , 4 1 ( 1 9 8 6 ) . 61. J.N.M. Heersche, C l i n . I n v e s t . Med., 5, 173 ( 1 9 8 7 ) . Jerome, D.B. Kimmel, J.A. M c A l i s t e r , and D.S. Weaver, C a l c i f . T i s s u e I n t . , 62. C . P . 206 ( 1 9 8 6 ) . K o r i t n i k , C a l c i f . Tissue Int., 63. L.C. M i l l e r , D . S . Weaver, J.A. M c A l i s t e r , and D.R. 38, 62 ( 1 9 8 6 ) . Faugere, M. Rush, R.M. F r i e d l e r , and H . H . M a l l u c h e , J . Bone Min. Res., 64. M.C. Suppl. 1, A b s t r a c t No. 303 ( 1 9 8 6 ) . 65. R.T. T u r n e r , N.H. B e l l , J. Bone Min. Res., 399 ( 1 9 8 6 ) . 66. 0.0. Thompson, G.A. Rodan, J. Bone Min. Res., 1, Suppl. 1, A b s t r a c t No. 96 ( 1 9 8 6 ) . Ignaszewski, C a l c i f . Tissue I n t . , 67. T.J. Wronski, PL.L. Lowry, C . C . Walsh, and L.A, 37, 324 ( 1 9 8 5 ) . 68. KH. Reddi i n "Bone and M i n e r a l Research, Annual 3," W.A. Peck, Ed., E l s e v i e r , Amsterdam, 1985, D . 27. S.K. N i s h i m o t o , C'.H. Chang, E. Gendler, W.F. S t r y k e r , and M.E. Nimni, C a l c i f . 69. 617 ( 1 9 8 5 ) . Tissue I n t . ,
27.
1,
.
36,
116,
149,
lo,
164,
., 137,
122,
102,
116,
2,
1,
1,
37,
Chap, 17 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107, 108. 109. 110. 111. 112. 113. 114. 115.
Bone Metabolism a n d Osteoporosis
Hayward, Caggiano
M. M a t s u s h i t a , T. Tsuboyama, R. Kasai, H. Okumura, T. Yamamuro, K. H i g u c h i , K. H i g u c h i , A. Kohno, T. Yonezu, A. U t a n i . M. Umezawa, and T. Takeda, Am. J. P a t h o l . , 125, 276 (1986). C. C. Johnston, Jr. and S. E p s t e i n i n " E n d o c r i n o l o g y o f Calcium Metabolism," J.A. Parons, Ed., Raven Press, New York, 1982, p. 467. B. Lund, J.G. Pedersen, C. Egsmore, B. Lund, Adv. Exp. Med. B i o l . , 149 (1984). V.J. H a j i r o u s s o u , and M. Webley, Ann. Rheum. D i s . , 43, 24 (1984). P;N. Sambrook, J.A. Eisman, M.G. Yeates, N.A. POCOCK S. E b e r l , and G.D. Champion, Ann. Rheum. D i s . , 45, 950 (1986). D.N. Kalu, R.R. H a a i n , and R. Cockerham, Age, 6, 114 (1983). C.H. Chesnut 111, J.L. I v e y , H.E. Gruber,-M. Matthews, W.B. Nelp, K. Sisom, and O.J. B a y l i n k , Metabolism, 32, 571 (1983). C. Tabuchi, D.J. Simmons, Fausto, J.E. R u s s e l l , I . Binderman, and L.V. A v i o l i , J. Clin. I n v e s t . , 637 (1986). C . Tabuchi, D.J. Simmons, A. Fausto, I . R . Reid, J.E. R u s s e l l , I. Binderman, and L.V. A v i o l i , J. Bone Min. Res. Suppl. 1, A b s t r a c t No. 98, (1986). H. F l e i s c h , "Bone and M i n e r a l Research, Annual l", W.A. Peck, Ed.; E x c e r p t a Medica, ( E l s e v i e r ) : Amsterdam , (1983); p. 319. H. Shinoda, G. Adamek, R. F e l i x , H. F l e i s c h , R. Schenk, and P. Hagan, C a l c i f . T i s s u e I n t . , 35, 87 (1983). D.J. Rowe a n d 7 . J . Hays, Metab. Bone Ois. & Rel. Res. 5 , 13 (1983). D.J. Rowe, Bone, 6, 433 (1985). P. H. Stevenson and J.R. Stevenson, C a l c i f . T i s s u e I n t . , 38, 227 (1986). J.M. D e l a i s s e . Y. Eeckhout, and G. Vaes, L i f e S c i . , 37, 2 3 1 (1985). K. Hoekman, S:E. Papapoulos, A.C.B. P e t e r s , 0.L.M; B i j o v e t , J. C1 n. E n d o c r i n o l . Metab., 61, 952 ( 1 9 8 5 ) . G.R. Snow, and C. Anderson. C a l c i f . T i s s u e I n t . . 38. 217 (1986). J.A. Kanis, and P.J. Meunier, Q. J. Med., New S e r z s L I I I ; 210; 145 ( 984). G . R . I . Power and J.D.L. Gay, C l i n . I n v e s t . Med., 9, 4 1 ( 1 9 8 n R. Lappalainen, M. K n u u t t i l a , S. Lammi, and ETM. Alhava, J. Chron c Dis., 36, 707 '( 1983). L.G. Strause, J.Y. R e g i n s t e r , P . Franchimont, and P. Saltman, J. Bone Min. Res. Suool. 1. A b s t r a c t 234 ( 1 9 8 6 ) . r J.R. W. Lau, and D.J. B a y l i n k , C a l c i f . T i s s u e I n t . , 40, F a r l e y , N.M. Tarbaux,'K.-H. 35 (1987). A.D. Kenny, C a l c i f . T i s s u e I n t . , 37, 126 ( 1 9 8 5 ) . W.S. Sly, D. Hewett-Emmett, M.P. Whyte, Y . - S . L. Yu, and R.E. Tashian, Proc. N a t l . Acad. S c i . USA, 80, 2752 ( 1 9 8 3 ) . C . V . Gay, W.J. M z l l e r , Science, 183, 432 (1974). H. Cao and C . V . Gay, E x p e r i e n t i a , x , 1472 ( 1 9 8 5 ) . R.E. Anderson, W.S.S. Jee, and O.M. Woodbury, C a l c i f . T i s s u e I n t . , 646 (1985). G.E. H a l l , and A.D. Kenny, C a l c i f . T i s s u e I n t . , 37, 134 (1985). G.E. H a l l , and A.D. Kenny, Pharmacology, 30, 3 3 9 7 1 9 8 5 1 . H.A. Simmons, L.G. Raisz, W.J. Thompson, P.S. Anderson, and G.A. Rodan, J. Bone Min. Res. 1., S U D D ~ . 1. A b s t r a c t 86 (1986). C.T. Stier; Jr., and H.D. I t s k o v i t z , Annu. Rev. Pharmacol. T o x i c o l , 3,101 ( 1 9 8 6 ) . C.M. P r o u d f i t , J.A.M.A., 252, (1984). R.O. Wasnich, R.J. B e n f a n K K. Yano, L. H e i l b r u n , and J.M. Vogel, N. E n g l . J. Med., 309, 344 ( 1 9 8 3 ) , R.D. Washnick, P.D. Ross, L.K H e i l b r u n . J.M. Voqel, K. Yano, and R.J. Benfante, O b s t e t . Gynecol., 67, 457 (1986). P.J. D r i n k a , and W T. N o l t e n , J. Am. G e r i a t r . SOC., 32, 405 ( 1 9 8 4 ) . K. Sakhaee, M.J. N i c a r , K. Glass, J.E. Z e r w e k K and C.Y.C. Pak, J . Clin. E n d o c r i n o l . Met., 59, 1037 ( 1 9 8 4 ) . R . Baron, L. N e f f , T . Roy, A. B o i s v e r t , and M. Caplan, C e l l , 46, 311 (1986). R.E. Anderson, O.M. Woodbury, and W.S.S. Jee, C a l c i f . T i s s u e Et., 2, 252 ( 1 9 8 6 ) . T. Akisaka, and C.V. Gay, C e l l T i s s u e Res., 57 (1986). J. Tuukkanen, H.K. Vaananen, C a l c i f . T i s s u e I n t . , 38, 123 (1986). J.K. Heath, S.J. A t k i n s o n , M.C. M e i k l e , and J.J,Reynolds, Biochim. Biophys. Acta, 802, 151 (1984). K. Otsuka, J. Sodek, and H. Limeback, Eur. J. Biochem., 145, 123 (1984). T.J. Chambers, and K. F u l l e r , J. C e l l S c i . , 76, 155 ( 1 9 8 r L.G. R a i s z and TJ. M a r t i n .in "Bone and M i n e r 5 Research, Annual 2," W.A. Peck, Ed., E l s e v i e r , Amsterdam, 1984, p. 286. 0. Hoffmann, K. K l a u s h o f e r , K. K o l l e r , and M. P e t e r l i k , P r o s t a g l a n d i n s , 30, 857 ( 1985). R.C. W i l l i a m s , M.K. J e f f c o a t , M.L. Kaplan, P. Goldhaber, H.G. Johnson, and W.J. Wechter. Science. 640 (1985)
171,
78,
1,
1,
-7
2,
. r
9,
227,
178
S e c t i o n IV-Endocrinology, Immunology, M e t a b o l i c D i s o r d e r s
J o h n s , Ed.
116. W . Lloyd, V.S. Fang, H. Wells, and A.H. Tashjian, Jr., Endocrinology, 85, 763 (1969). 163 ( 1 9 7 1 ) . 117. V.S. Fang. C. Minkin, P. Goldhaber, Science, 118. J.C. Robin, S.D. Sharma, K. Francis, M. Rosenstein, R. Moore, J.A. Vida, C.C. Thomas, Jr., and J.L. Ambrus, J. Med., 11, 1 5 (1980). 119. L.G. Raisz. C. Alander, C. OnkelinxTand G.A. Rodan, Calcif. Tissue Int., 37, 556 ( 1985). 120. J.C. Robin, M.J. Brown, N. Weinfeld, R.M. Dziak. Calcif. Tissue Int., 2 , 194 ( 1984). 121. S.Y. Ly, C . Rebut-Bonneton, and L. Miravet, Horm. Metab. Res., 152 (1985). 122. G. Eilon, and L.G. Raisz, Calcif. Tissue Int., 34, 506 (1982). 123. U. Lerner, and G. Granstrom, Eur. J. Pharmacol., 105, 1 ( 1 9 8 4 ) . 124. U . Lerner, and G.T. Gustafson, Experientia, 35, 5 F ( 1 9 7 9 ) . 125. M.T. Garba, and P.J. Marie, Calcif. Tissue Iz.,38, 296 ( 1 9 8 6 ) . 126. T. Komoda, E . Ikeda, Y . Nakatani, Y. Sakagishi, N. Maeda, T. Kato, and M. Kumegawa, Biochern. Pharmacol., 34, 3885 (1985). 127. P. Goldhaber, and L. Ebadjija, Proc. SOC. Exp. Biol. Med., 169, 105 ( 1 9 8 2 ) . 128. M.L. Tyan, Proc. SOC. Exp. Biol. Med., 179, 240 ( 1 9 8 5 ) . 129. G.A. Roden, L.A. Bourret, A. Harvey, a n m . Mensi, Science, 189, 467 ( 1 9 7 5 ) . 130. N.S. Krieger, T.S S t a p p p n h e c k , and P.H. Stern, J. Clin. I n v e x , 79, 444 (1987) 131. N.S. Krieger, V.M. Stathopoulos, and P.H. Stern, Circulation, 59 ( 1 9 8 6 ) . 132. J.C. Robin, and J.L. Ambrus, J. Med., 14, 137 ( 1 9 8 3 ) . 133. J.C. Robin, J.L. Ambrus, J. Med., 15, 519 ( 1 9 8 4 ) . 134. J.C. Robin, and J.L. Ambrus, J. M e x , 13, 465 ( 1 9 8 2 ) . 135. I . Yamazaki, and M. Kinoshita, Life S c r , 2 , 1535 ( 1 9 8 6 ) . 136. I . Yamazaki, A. Shino, Y . Shimizu, R. Tsukuda, Y . Shirakawa, and M. Kinoshita, Life Sci., 2 , 951 ( 1 9 8 6 ) . 137. R.P. Warrell, Jr., R.S. Bockman, C.J. Coonley, M. Isaacs, and H. Staszewski, J. Clin. Invest., 73, I487 ( 1 9 8 4 ) . 138. R.P. Warrell, J C , U S Patent 4,529,593, 1985.
172,
17,
z,-m,
E n d o c r i n o l o g y , Immunology and M e t a b o l i c D i s o r d e r s
E d i t o r : W i l l i a m F. Johns, S t e r l i n g - W i n t h r o p Research I n s t i t u t e , Rensselaer, New York 12144 Chapter 17
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M e d i c i n a l Chemistry O p p o r t u n i t i e s i n Bone M e t a b o l i s m and O s t e o p o r o s i s
M a r s h a l l A. Hayward and Thomas J . Caggiano A y e r s t L a b o r a t o r i e s Research I n c . , CN 8000, P r i n c e t o n , NJ 08540 I n t r o d u c t i o n - Bone i s a dynamic t i s s u e which c o n t i n u o u s l y undergoes remodel 1 i n g ( 1 , 2 ) . A p p r o x i m a t e l y 10% o f c o r t i c a l bone ( t h e dense, h i g h l y m i n e r a l i z e d bone w h i c h comprises t h e s h a f t s o f l o n g bones) and 20 t o 40 % o f t h e t r a b e c u l a r bone ( c a n c e l l o u s bone f o u n d i n t h e i n t e r i o r o f v e r t e b r a e and i n t h e m e d u l l a r y space of l o n g bones) i s r e m o d e l l e d each year i n the healthy adult. I n t h i s process m u l t i n u c l e a r o s t e o c l a s t s r e s o r b bone, r e l e a s i n g m i n e r a l and m a t r i x p e p t i d e c o n s t i t u e n t s . T h i s r e s o r p t i o n i s l i n k e d t o a r e b u i l d i n g process i n which o s t e o b l a s t s r e p l a c e eroded bone t i s s u e (see b e l o w ) . Normal Breakdownof Bone
.. .
Bone-absorbmgcells called osteoclasts lit between boneliningcells, above, and dig cavities. below. in the inner sudace of the bone Release0 bone proteins and other substances then I r w r rebuildingprocess
OsteoMasts move into newly created bone m v q . above. and begin rebuildmg bone. hrst by producinga Collagen framework and men mineralizingit with crystalsof cakium and phosphorus In osteopcfosis. less bone IS rebuln than destroyed
New Born
Adolph Brotman; c o p y r i g h t 0 1 9 8 7 by The New York Times Company, R e p r i n t e d by p e r m i s s i o n .
O s t e o p o r o s i s (OP) i s a d e b i l i t a t i n g p r o g r e s s i v e loss o f bone m i n e r a l which u l t i m a t e l y m a n i f e s t s i t s e l f i n e l e v a t e d f r a c t u r e r a t e s , g e n e r a l l y among t h o s e o v e r age 45 ( 3 ) . OP i s most p r e v a l e n t among postmenopausal women, b u t a f f e c t s b o t h sexes. C u r r e n t e s t i m a t e s suggest t h a t 15 t o 20 m i l l i o n persons i n t h e U. S. a r e a f f l i c t e d . More p a t i e n t s w i l l be i d e n t i f i e d as t h e l i f e span i n c r e a s e s . T r a d i t i o n a l l y , modulat i o n o f t h e e n d o c r i n e system has been t h e p r e f e r r e d approach t o t h e management o f OP ( 4 - 7 ) . T h i s r e p o r t w i l l p r o v i d e an o v e r v i e w o f t o p i c s i n p r e c l i n i c a l bone metabolism r e s e a r c h as w e l l as s i g n i f i c a n t new developments i n c l i n i c a l management o f OP. C l i n i c a l Developments - The 1983 NIH consensus c o n f e r e n c e on OP has served t o f o c u s n a t i o n a l a t t e n t i o n on t h e c l i n i c a l management o f OP ( 8 ) . T h i s c o n f e r e n c e recommended t h e use o f postmenopausal e s t r o g e n ANNUAL REPORTS IN MEDICINAL CHEMISTRY-22
Copyright 0 1987 by Academic Press, Inc. All rights of reproduction in any form reserved.
170 Section IV-Endocrinology, Immunology, Metabolic Disorders Johns, Ed. -
replacement t h e r a p y , which has been shown t o d e l a y t h e o n s e t and p r o g r e s s i o n o f OP ( 9 - 1 1 ) . Coupled w i t h adequate d i e t a r y c a l c i u m and e x e r c i s e , t h i s regimen r e p r e s e n t s t h e f i r s t l i n e o f defense a g a i n s t bone demineralization. However, r e p l e n i s h m e n t o f l o s t bone i s n o t a c h i e v e d by t h i s s t r a t e g y . P r o p h y l a c t i c b e n e f i t has a l s o been d e r i v e d f r o m t h e use o f p r o estagens such as n o r e t h i s t e r o n e a l o n e and i n c o m b i n a t i o n w i t h e s t r o g e n s q12-16). P a r a t h y r o i d hormone (PTH) a c u t e l y s t i m u l a t e s bone r e s o r p t i o n v i t r o , as w e l l as a c t i v a t i n g bone r e m o d e l l i n g i n v i v o ( 7 ) . A therap e u t i c r e imen c o n s i s t i n g o f PTH f o l l o w e d b y 1 , 2 5 - d i h y d r o x y v i t a m i n D3 (1,25D3; 17 t r e a t m e n t shows promise as a means t o i n c r e a s e bofie m i n e r a l (17). Progress i n t h e a r e a o f PTH a n t a g o n i s t s i s l i k e l y t o y i e l d i n s i g h t i n t o t h i s approach ( 1 8 ) . V i t a m i n D m e t a b o l i t e s such as 1 may p l a y a d i r e c t , p i v o t a l r o l e i n t h e development o f OP ( 1 9 , 2 0 ) . These m e t a b o l i t e s r e g u l a t e t h e f u n c t i o n o f d i f f e r e n t i a t e d human o s t e o b l a s t s , monocytes and lymphocytes, s e r v i n g t o m e d i a t e bone m e t a b o l i s m a t s e v e r a l l e v e l s (21,22). C a l c i t o n i n (CT), known t o decrease t h e bone r e s o r p t i o n process and have d i r e c t i n h i b i t o r y e f f e c t s on o s t e o c l a s t s i n v i t r o ( 2 3 ) , has shown e f f i c a c y i n one and two y e a r t r i a l s (24,25). I n m o n to d i r e c t e f f e c t s on bone r e s o r p t i o n , CT may s e r v e t o i n c r e a s e bone format i o n by a l t e r i n g v i t a m i n D3 m e t a b o l i s m ( 2 6 ) . S i g n i f i c a n t drawbacks o f CT t h e r a p y a r e t h e r e q u i r e m e n t f o r p a r e n t e r a l a d m i n i s t r a t i o n and p o t e n t i a l a n t i g e n i c i t y o f t h e p e p t i d e ; however, salmon CT has been s u c c e s s f u l l y d e l i v e r e d i n t r a n a s a l l y . Human CT i s a v a i l a b l e (27,28). CT l e v e l s a r e u n a f f e c t e d by e s t r o g e n t h e r a p y and i t i s t h o u h t t h a t p o s t menopausal OP i s n o t m e d i a t e d by a p r i m a r y CT d e f i c i e n c y ?29,30). ~
I n a two-year s t u d y , d i e t a r y c a l c i u m s u p p l e m e n t a t i o n a l o n e was i n s u f f i c i e n t t o guard a g a i n s t t h e development of postmenopausal GP (31). Adequacy o f c a l c i u m i n t a k e can, however, s e r v e t o r e t u r n an i n d i v i d u a l t o p o s i t i v e calcium balance (32). The i m p a c t o f c a l c i u m d e f i c i e n c y on p a t i e n t response t o t h e r a p y i s an i m p o r t a n t concern i n t h e d e s i g n of c l i n i c a l s t u d i e s ( 3 3 ) . Calcium supplements have, however, been shown t o i n c r e a s e t h e c a l c i u m b a l a n c e o f a d o l e s c e n t g i r l s o v e r a two week span, s u g g e s t i n g t h a t adolescence i s a c r i t i c a l p e r i o d f o r skeletal calcium accretion (34). Nevertheless, t h e n o t i o n t h a t i n c r e a s i n g s k e l e t a l mass p r i o r t o menopause w i l l p r o t e c t against o s t e o p o r o s i s has been c a l l e d i n t o q u e s t i o n ( 3 5 ) . F a m i l y h i s t o r y and s k e l e t a l a t t r i b u t e s a r e i m p r e c i s e , b u t a r e o f t e n as p r e d i c t i v e as more s o p h i s t i c a t e d t e c h n i q u e s i n p r o v i d i n g a c c u r a t e OP r i s k assessment (36). W h i l e d e t e r m i n a t i o n s o f bone m i n e r a l c o n t e n t i n l o n g i t u d i n a l s t u d i e s a r e u s e f u l , t h e i n f o r m a t i o n may come t o o l a t e t o benefit the individual patient. Assays (e.g., serum o s t e o c a l c i n measurements) have appeared, o n l y t o be deemed more a p p r o p r i a t e as i n d i c a t o r s of t h e s t a t u s o f bone t u r n o v e r ( 3 7 ) . Several assays c u r r e n t l y r e c e i v i n g a t t e n t i o n a r e a l u t e i n i z i n g hormone r e l e a s i n g hormone (LHRH) i n d u c e d menopause, a l k a l i n e phosphatase isozyme measurements, serum a c i d phosphatase a c t i v i t y , serum v i t a m i n K l e v e l s , and T lymphoc y t e s u b s e t a n a l y s e s (38-42).
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P r e c l i n i c a l Research U n d e r s t a n d i n g t h e mechanism by which m i n e r a l homeostasis and mechanical f u n c t i o n a r e m a i n t a i n e d i s c r i t i c a l t o t h e development o f improved t h e r a p y f o r OP ( 4 3 ) . The o r i g i n , development and d i f f e r e n t i a t i o n of bone c e l l s i s an i n t e n s e l y i n v e s t i g a t e d t o p i c (44,451. I t has been proposed t h a t o s t e o b l a s t s a r e key r e g u l a t o r y c e l l s i n bone. O b s e r v a t i o n s c o n c e r n i n g hormone e f f e c t s s u p p o r t t h i s n o t i o n
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(46-48). C y t o k i n e s produced b y macrophages o r c e l l s o f t h e immune system may p r o v i d e a d d i t i o n a l l e v e l s of c o n t r o l on bone r e m o d e l i n g (49-56). As more i s l e a r n e d a b o u t t h e development and d i f f e r e n t i a t i o n of o s t e o c l a s t s and t h e r o l e o f c a l c i t r o p i c hormones on bone c e l l a c t i v i t y , a d d i t i o n a l approaches t o t h e m o d u l a t i o n o f m i n e r a l homeostasis w i l l be r e a l i z e d . I n t h i s r e g a r d , bone m a t r i x i t s e l f i s a r i c h s o u r c e of t h e s e a c t i v i t i e s and many p e p t i d e f a c t o r s i s o l a t e d f r o m bone have been r e p o r t e d t o modulate bone metabol ism (57-59). Animal Models - W h i l e t h e r e a r e many a c c e p t e d i n v i t r o assays f o r bone r e s o r p t i o n and f o r m a t i o n , p r e c l i n i c a l i n v i v o models o f bone m e t a b o l i s m a r e s t i l l b e i n g e s t a b l i s h e d (60,611. S t u d i e s i n non-human p r i m a t e s i n d i c a t e t h a t o v a r i e c t o m y produces a n e t decrease i n b o t h i l i a c and v e r t e b r a l t r a b e c u l a r bone (baboons and cynomolgus monkeys respectively) (62,63). Canines s u b j e c t e d t o o v a r i e c t o m y showed a l o w e r bone m i n e r a l content i n the i l i a c c r e s t than controls, w i t h the d e f i c i t ascribed t o depressed bone f o r m a t i o n , a r e s u l t o f decreased o s t e o b l a s t a c t i v i t y ( 6 4 ) . A l i m i t a t i o n o f t h e s e models i s t h e t i m e (months) r e q u i r e d f o r t h e development o f OP; t h u s , a s i g n i f i c a n t c h a l l e n g e t o i n v e s t i g a t o r s i n t h e f i e l d i s t o d e v e l o p s h o r t e r - t e r m models o f OP. H i s t o l o g i c changes i n r o d e n t s i n d u c e d by tenotomy o r d e n e r v a t i o n o c c u r w i t h i n days, whereas o v a r i e c t o m y i n d u c e d bone loss o c c u r s o v e r a span of weeks (65-67). Such models have t h e p o t e n t i a l t o b r i d g e t h e gap between i n v i t r o and extended i n v i v o s t u d i e s i n l a r g e r s p e c i e s . I m p l a n t s o f bone m a t r i x can be u t i l i z e d t o s t u d y endochondral o s s i f i c a t i o n (68,69). Loss o f bone m i n e r a l i s a c c e l e r a t e d i n some s t r a i n s of m i c e ( w i t h o u t s u r g i c a l o r m e t a b o l i c c h a l l e n g e ) , which may p r o v i d e a model f o r s e n i l e OP ( 7 0 ) . C o r r e l a t i o n o f t h e s e models w i t h r e g a r d t o human d i s e a s e r e p r e s e n t s a major challenge. Pharmacologic e f f e c t o r s o f bone m e t a b o l i s m - A l a r g e number of s t r u c t u r a l l y d i v e r s e compounds have been r e p o r t e d t o m e d i a t e bone metabolism. I t i s i m p o r t a n t t o n o t e t h e dose l e v e l used i n a l l o f t h e cases c i t e d below because t h e l e v e l r e q u i r e d t o e l i c i t a response i s o f t e n w e l l above o r w e l l below t h o s e r e q u i r e d t o e l i c i t o t h e r t y p e s of pharmacologic a c t i v i t y . E n d o c r i n e Agents - E n d o c r i n e m e d i a t o r s o f bone m e t a b o l i s m a r e g e n e r a l l y sex o r c a l c i t r o p i c hormcnes ( 7 1 ) . However, r e c e n t r e p o r t s o f bone s p a r i n g e f f e c t s o f c o r t i c o s t e r o i d s and t h e modest t o v e r y l o w r i s k o f OP i n p a t i e n t s on l o w dose p r e d n i s o l o n e f o r r h e u m a t o i d a r t h r i t i s a r e encouraging (72-74). I n t h e case o f a n a b o l i c s t e r o i d s t h e r e s u l t s a r e mixed. Dehydroepiandrosterone f a i l e d t o a m e l i o r a t e o v a r i e c t o m y i n d u c e d OP i n r o d e n t s ( 7 5 ) y e t s t a n a z o l o l ( 2 ) caused a n e t i n c r e a s e i n t o t a l body c a l c i u m i n a 29 month s t u d y i n postmenopausal OP women ( 7 6 ) . Bone
172 S e c t i o n IV-Endocrinology, Immunology, M e t a b o l i c D i s o r d e r s Johns, Ed. f o r m a t i o n r a t e s were m a r g i n a l l y i n c r e a s e d i n t h e s t a n a z o l o l t r e a t e d group r e l a t i v e t o b a s e l i n e measurements, b u t b o t h t e s t and c o n t r o l groups were t r e a t e d w i t h c a l c i u m , and showed a s l i g h t i n c r e a s e r e l a t i v e an a n a l o g o f improved t h e t o baseline. Dihydrotachysterol a b i l i t y o f marrow s t r o m a l c e l l s f r o m o v a r i e c t o m i z e d r a t s t o p r o l i f e r a t e i n v i t r o , as w e l l as i n c r e a s i n g o s t e o g e n i c parameters i n i m p l a n t g r a f t s (7t).In t h e same model system, e s t r o g e n i n c r e a s e d t h e i n v i t r o c o l o n y f o r m i n g a b i l i t y o f marrow s t r o m a l c e l l s , b u t d i d n o t i n c r e a s e t h e & v i v o osteogenic p r o p e r t i e s o f these c e l l s (78).
(z),
1,
Bisphosphonates - The bisphosphonates ( 4 ) , c a r b o n analogs o f pyrophosphate, have been e x t e n s i v e l y e x p l o r e d (79,80). They g e n e r a l l y i n h i b i t b o t h t h e c r y s t a l l i z a t i o n and d i s s o l u t i o n o f c a l c i u m phosphate i n v i t r o . Etidronate (5) i s the strongest i n h i b i t o r s t u d i e d . When t h e s u b s t i t u e n t s a r e h a l o o x 6 gens (6,7)one sees s t r o n g i n h i b i t i o n of bone r e s o r p t i o n . 7 i n h i b i t s bone r e s o r p .=;+Lo 4 I I tion and remodeTing w i t h o u t i n h i b i t i n g HO Y O H m i n e r a l i z a t i o n (81, 8 2 ) . Bisphosphonates X Y a r e r e p o r t e d t o i n h i b i t macrophage m i g r a 5 OH CH, t i o n ( 8 3 ) . S t u d i e s on t h e a b i l i t y o f 6 and 8 t o i n h i b i t the formation o f resorp6 CI CI 7 F F t i o n Tacunae and PTH i n d u c e d s e c r e t i o n o f 8 OH (cH,),NH, lysosomal h y d r o l a s e suggest t h e s i t e o f a c t i o n t o be t h e o s t e o c l a s t as opposed t o t h e o s t e o b l a s t (84). 8 i s a l s o useful i n t r e a t i n g j u v e n i l e OP, a d i s e a s e i n which t h e p r i m a r y d e f e c t i s u n a t t e n u a t e d a c t i v i t y o f metaphyseal o s t e o c l a s t s (85). F l u o r i d e - A u s e f u l t h e r a p e u t i c a g e n t would i n c r e a s e bone mass as w e l l as decrease t h e f r a c t u r e r a t e . F l u o r i d e may r e p r e s e n t such an approach t o t h e c l i n i c a l management o f OP. I n t h e spayed b e a g l e dog, h i s t o l o g i c e v a l u a t i o n o f bone showed a number o f f l u o r i d e e f f e c t s ( 8 6 ) . These i n c l u d e a c t i v a t i o n o f bone t u r n o v e r , and a l t e r a t i o n s o f t h e d i f f e r e n t i a t i o n and a c t i v i t y of b o t h o s t e o b l a s t s and o s t e o c l a s t s . Increased o s t e o b l a s t i c a c t i v i t y i n v i t r o as w e l l as bone f o r m a t i o n i n v i v o a r e r e s u l t s of f l u o r i d e exposure. However, f l u o r i d e dose and t h e a v a i l a b i l i t y of m i n e r a l c o n s t i t u e n t s must be p r o p e r l y m a i n t a i n e d t o a v o i d t h e development of an o s t e o s c l e r o t i c s k e l e t o n ( 8 7 ) . I n one s t u d y , o n l y t h o s e p a t i e n t s d e v e l o p i n g s k e l e t a l f l u o r o s i s showed a decrease i n vertebral fracture r a t e (88). F l u o r i d e may a l t e r t r a c e m i n e r a l m e t a b o l i s m (Zn, Mn) w i t h i n bone, e f f e c t s t h a t may have l o n g t e r m consequences (89,90). Some untoward s i d e e f f e c t s o f sodium f l u o r i d e t h e r a p y may be a l l e v i a t e d b y t h e a d m i n i s t r a t i o n of monofluorophosphate (MFP), w h i c h has an a c t i v i t y p r o f i l e s i m i l a r t o t h a t o f sodium f l u o r i d e i n v i t r o . Workers have demonstrated t h e a b i l i t y o f a l k a l i n e phosphatase i n c h i c k s k e l e t a l t i s s u e t o h y d r o l y z e MFP, t h u s p r o v i d i n g f r e e f l u o r i d e a t s k e l e t a l s i t e s (91). Enzyme I n h i b i t i o n - The i n v o l v e m e n t o f t h e enzyme c a r b o n i c anhydrase 1EC4.2.1.11 i n t h e bone r e s o r p t i o n process has been extended b y o b s e r v a t i o n s s u g g e s t i n g t h a t l i m b d i s u s e a t r o p h y may be a l l e v i a t e d by a d m i n i s t r a t i o n of c a r b o n i c anhydrase i n h i b i t o r s ( 9 2 ) . An i n s u f f i c i e n c y i n c a r b o n i c anhydrase was i d e n t i f i e d as t h e p r i m a r y d e f e c t i n o s t e o p e t r o s i s , a d i s e a s e c h a r a c t e r i z e d b y i n s u f f i c i e n t bone r e s o r p t i o n ( 9 3 ) . Carbonic anhydrase has been d e t e c t e d i n t h e o s t e o c l a s t i n p h y s i o l o g i c a l l y important Quantities (94). The enzyme i s a s s o c i a t e d w i t h t h e a c t i v e r e s o r b i n g zone of t h e o s t e o c l a s t a f t e r exposure t o PTH, and
Chap. 17
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Hayward, C a g g i a n o
173
becomes d i s p e r s e d t h r o u g h o u t t h e c e l l a f t e r exposure t o CT ( 9 5 ) . An i n c r e a s e i n t h e a c i d i t y of o s t e o c l a s t s i s s t i m u l a t . e d by PTH, a process p a r t i a l l y i n h i b i t e d by c a r b o n i c anhydrase i n h i b i t o r s ( 9 6 ) , such as ( 9 ) . 9 i n h i b i t s both a c e t a z o l amide S p r o s t a g l a n d i n E2 and T,25D3 stimulated CH3C0NH% k s 0 z N H 2 bone r e s o r p t i o n (97,981. It i s noteworthy 9 N-N t h a t improvement o f c a r b o n i c anhydrase i n h i b i t i o n i s not necessarily well correl a t e d w i t h a s i m i l a r improvement i n bone r e s o r p t i o n i n h i b i t i o n ( 9 9 ) . T h i a z i d e d i u r e t i c s , which a r e r e c o g n i z e d f o r c a l c i u m r e t e n t i o n p r o p e r t i e s , a r e a l s o c a r b o n i c anhydrase i n h i b i t o r s ; t h e s e compounds have r e c e i v e d some a t t e n t i o n as p o t e n t i a l a n t i o s t e o p o r o t i c s (100,103). Other c o m p l i c a t i o n s of t h i a z i d e t h e r a p y may a r i s e , however, such as reduced i n t e s t i n a l c a l c i u m a b s o r p t i o n (104,105). E x a m i n a t i o n o f t h e mechanism by which o s t e o c l a s t s g e n e r a t e an a c i d i c environment has demonstrated t h e p r e sence o f an ATPase i n t h e membrane o f t h e s e c e l l s (106,107). T h i s enzymatic a c t i v i t y appears t o be f u n c t i o n a l l y and t e m p o r a l l y a s s o c i a t e d w i t h t h e r e s o r p t i o n process (108). Omeprazole a pharmacologic i n h i b i t o r o f K+/H+ ATPase known t o i n h i b i t g a s t r i c a c i d s e c r e t i o n , i n h i b i t s bone r e s o r p t i o n i n v i t r o ( 1 0 9 ) .
(g),
Collagenase i s s y n t h e s i z e d and s e c r e t e d as p r o c o l l a g e n a s e by o s t e o b l a s t s i n response to resorption stimulators. Collagenase i n h i b i t o r s a r e s y n t h e s i z e d and s e c r e t e d as w e l l (110,111). I n an e l e g a n t s e r i e s of e x p e r i m e n t s , t h e a b i l i t y o f i s o l a t e d o s t e o c l a s t s t o degrade bone s u b s t r a t e was markedly enhanced by p r e - i n c u b a t i o n o f bones w i t h c a l v a r i a l c e l l s o r w i t h exogenous c o l l a g e n a s e ( 1 1 2 ) . Calvarial c e l l s a l o n e a r e a b l e t o degrade o s t e o i d , b u t n o t m i n e r a l i z e d t i s s u e . Taken t o g e t h e r , t h e s e o b s e r v a t i o n s s u p p o r t t h e n o t i o n t h a t o s t e o b l a s t i c c e l l s may p h y s i c a l l y p r e d i s p o s e bone m i n e r a l t o f u r t h e r d i g e s t i o n by o s t e o c l a s t s (see a1 s o t h e accompanying c h a p t e r on o s t e o a r t h r i t i s )
.
P r o s t a g l a n d i n E2 i s a s t i m u l a t o r o f bone r e s o r p t i o n and t h u s may c o n t r i b u t e t o bone l o s s , p a r t i c u l a r l y when a s s o c i a t e d wit,h COOH i n f l a m m a t i o n (e.g., i n periodontal d i s ease; 113,114). Flurbiprofen has 11 been shown t o be a p o t e n t i n h i b i t o r o f a l v e o l a r bone loss i n beagles ( 1 1 5 ) . C l i n i c a l s t u d i e s a r e i n p r o g r e s s . H3
(E),
- T h i o p h e n e - 2 - c a r b o x y l i c a c i d (TCA) was Thiophene c a r b o x y l i c a c i d s o r i g i n a l l y d e s c r i b e d as a hypoglycemic antilipolytic agent with hypocalcemic and hypophosphatemic a c t i v i t y ( 1 1 6 ) . Subsequent s t u d i e s showed t h a t TCA i n h i b i t e d r e s o r p t i o n o f n e o n a t a l mouse c a l v a r i a i n v i t r o (117). BL5583 ( 1 2 ) and BL5593 ( 1 3 ) have been shown t o be a c t i v e a g a i n s t h e p a r i n - a c c e l e r a t a OP ( 1 1 8 ) . Recent work has extended t h i s c l a s s t o i n c l u d e aza analogs, i n d o l e - 2 - c a r b o x y l i c a c i d and c a r b a z o l e - 1 - c a r b o x y l i c The most a c i d ( 1 4 ) , as i n h i b i t o r s o f PTH s t i m u l a t e d bone r e s o r p t i o n . 1 2 ) has been shown t o t r a n s i e n t l y i n h i b i t potent-compound s t u d i e d (c e l l u l a r Ca++ uptake ( 1 1 9 ) , y e t n o t a l t e r i n t r a c e l l u l a r CAMP ( 1 2 0 ) . I n t e r e s t i n g l y , i n a s e p a r a t e s t u d y , t h e Ca++ channel b l o c k e r d i l t i a z e m was shown t o be i n e f f e c t i v e as an i n h i b i t o r o f u n s t i m u l a t e d bone r e s o r p t i o n , y e t was e f f e c t i v e as an i n h i b i t o r o f 1,25D3 s t i m u l a t e d bone r e s o r p t i o n ( a s j u d g e d by 45Ca and h y d r o x y p r o l i n e r e l e a s e ; 1 2 1 ) .
(5)
174
S e c t i o n IV-Endocrinology,
Immunology, M e t a b o l i c D i s o r d e r s
J o h n s , Ed. OCH,
~
c
o
o
H
12
13 14
X
S NH
R
2-COOH 1-COOH
15
-
_Lysosomal Enzyme Release I n h i b i t o r s (LERI) LERI ( c h l o r o q u i n e , hydroxys t i l b a m i d i n e , dapsone, and l e v a m i s o l e (L-16) have beer: demonstrated t o inhibit bone r e s o r p t i o n i n v i t r o (In). U n l i k e i t s a n t h e l m i n t i c a c t i v i t y , levamisole's a b i l i t y t o i n h i b i t resorption i s not stereospecific (123). Dexamisole (D-16) and b r o m o t e t r a m i s G l e have similar activity. Levamisole and i t s congeners inhibit lactate p r o d u c t i o n and a1 k a l i n e phosphatase (124,125). B o t h enantiomers of a r e a p p r o x i m a t e l y 10 f o l d more a c t i v e t h a n l e v a m i s o l e as i n h i b i t o r s o f 45Ca r e l e a s e f r o m c u l t u r e d e x p l a n t s . These compounds may a c t d i r e c t l y on o s t e o c l a s t s t o i n h i b i t r e s o r p t i o n , r a t h e r t h a n by a r e c e p t o r m e d i a t e d event. P h e n o t h i a z i n e d e r i v a t i v e s have a l s o been shown t o i n h i b i t a l k a l i n e phosphatase i n o s t e o b l a s t i c c e l l s (126). For example, promethazine n o t o n l y i n h i b i t s r e s o r p t i o n (127) b u t leads t o r e t e n t i o n o f bone mass i n a g i n g m i c e ( 1 2 8 ) . Promethazine e f f e c t s have been a t t r i b u t e d t o d i r e c t i n h i b i t i o n o f macrophage a c t i v i t y (e.g., p r o s t a g l a n d i n r e l e a s e and p h a g o c y t o s i s ) .
(17)
(17)
(18)
16 17
R=H
R = Br
I n c i d e n t a l R e p o r t s - The compounds r e p o r t e d h e r e have been t h e s u b j e c t s i n g l e papers on a c t i v i t y i n bone metabolism. F o r t h e most p a r t , t h e mode o f a c t i o n i s n o t w e l l understood. of
cAMP p h o s p h o d i e s t e r a s e has been i d e n t i f i e d i n bone t i s s u e (129). S e v e r a l r e p o r t s have appeared on t h e e f f e c t o f PDE i n h i b i t o r s on bone m e t a b o l i c processes. The c a r d i o t o n i c agent m i l r i n o n e (19) has been demonstrated t o e l i c i t an i n c r e a s e i n bone r e s o r p t i o n i n v x r o ( 1 3 0 ) , i n c o n t r a s t t o amrinone an i n h i b i t o r o f r e s o r p t i o n . P e n t o x i f y l l i n e (21), a methyl xanthine d e r i v a t i v e , i n c r e a s e d Ca++ u p t a k e and cAMP The l e v e l s r e q u i r e d p r o d u c t i o n i n r o d e n t o s t e o b l a s t - l i k e c e l l s (132). f o r Ca++ u p t a k e were w e l l below t h o s e needed t o i n c r e a s e cAMP p r o d u c t i o n ( 1 3 3 ) . T h i s was c o n s t r u e d t o suggest a mechanism n o t dependent on PDE inhibition. BL3459 ( 2 2 ) and BL4160 ( 2 3 ) , were report.ed t o i n h i b i t h e p a r i n i n d u c e d OP i n f i c e ( 1 3 4 ) . I p r i n a v o n e (24) i s r e p o r t e d t o augment t h e a b i l i t y o f e s t r o g e n t o e l i c i t CT s e c r e t i o n i n t h e response t o a serum c a l c i u m c h a l l e n g e (135). I n r a t s w i t h g l u c o c o r t i c o i d i n d u c e d OP, 24 suppressed r e s o r p t i o n i n t h e rnetaphyses and p o s s i b l y i n h i b i t e d bone G s s i n t h e diaphyses ( 1 3 6 ) . G a l l i u m n i t r a t e has shown u t i l i t y i n t h e a m e l i o r a t i o n o f h y p e r c a l c e m i a a s s o c i a t e d w i t h m a l i g n a n c y (137,138).
(g),
Chap. 17
Bone M e t a b o l i s m and O s t e o p o r o s i s
H
19 20
X R CN CH, NH, H
Hayward, C a g g i a n o
175
24
RQ o -J-
Summary - I n t h e 5 y e a r s s i n c e t h e l a s t r e v ew o f bone rnetabo ism appeared i n t h i s s e r i e s , o u r knowledge o f b a s i c bone m e t a b o l i s m has g r e a t l y increased (4). P r a c t i c a l i n v i t r o and n v i v o models . a .r e - now a v a i l a b l e t o s e r v e as a b a s i s f o r t h e s t u d y o f sy t h e t i c m e d i a t o r s o f bone metabolism. Thus, t h e development of n o v e l - t h e r a p e u t i c approaches t o t h e c l i n i c a l management o f d i s e a s e represents a significant opportunity i n medicinal chemistry. REFER E N c E s
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
11. 12. 13.
14. 15. 16. 17. 18. 19.
20.
21. 22. 23. 24. 25. 26.
H.M. F r o s t i n "Bone and M i n e r a l Research, Annual 3," W.A. Peck, Ed., E l s e v i e r , Amsterdam, 1985, p. 49. Peck, Ed., Excerpta P.J. Meunier i n "Bone and M i n e r a l Research, Annual 1," W.A. Medica, E l s e v i e r , Amsterdam, 1983, p. 191. B.J. C u l l i t o n , Science, 235, 833 ( 1 9 8 7 ) . F.R. S i n g e r i n " A n n u a r R e p o r t s i n M e d i c i n a l C h e m i s t r y " , H.-J. Hess, Ed., Academic Press, New York, 1981, V o l . 17, C h a p t e r 26. H.F. Gruber, N. B r a u t h a r , Nephron, 38, 76 ( 1 9 8 4 ) . A.D. Woolf, A.S.J. Dixon, Drugs, 28,-565 (1984). Med., 309, 29 ( 1 9 8 3 ) . L.G. R a i s z , B.E. Kream, N. Engl . W.A. Peck, Chairman, J.A.M.A., 252, 799 (lm). R . L i n d s a y , O.M. H a r t , and D . M . T a r k , O b s t e t . Gynecol., 63, 759 ( 1 9 8 4 ) . B. E t t i n g e r , H.K. Genant, and C . E . Cann, Ann. I n t e r n . Med, 319 ( 1 9 8 5 ) . F.W. L a f f e r t y , 0.0. Helmuth, M a t u r i t a s , 7, 147 ( 1 9 8 5 ) . C. C h r i s t i a n s e n , A c t a Pharmacol. T o x i c o l T , 59, Sup. V I I , 305 ( 1 9 8 6 ) . P.L. S e l b y , M. Peacock, S.A. B a r k w o r t h , W.BrBrown, and G.A. Taylor, C l i n . Sci., 69, 265 ( 1985). C h r i s t i a n s e n , B.J. R i i s , L . N i l a s , and P. Rodbro, L a n c e t , 1. 800 ( 1 9 8 5 ) . P.L. Selby, M. Peacock, L a n c e t , 2, 1194 ( 1 9 8 5 ) . H . I . A b d a l l a , D.M. H a r t , R . L i n d s a y , I . Leggate, and A. Hooke, O b s t e t . Gynecol., 66, 789 ( 1 9 8 5 ) . K M . S l o v i k , M.A. D a l y , S.H. O o p p e l t , J.T. P o t t s , D . I . R o s e n t h a l , and R.M. Neer, J . Bone Min. Res. S u p p l . 1, A b s t r a c t No. 169, ( 1 9 8 6 ) . M. R o s e n b l a t t , N. E n g l . J. Med., 315, 1004 ( 1 9 8 6 ) . K.S. T s a i , H. Heath 111, R. Kumar, and B.L. Riggs, J. C l i n . I n v e s t . , 1668 (1984). E.S. O r w o l l , O.E. M e i e r , J. C l i n . E n d o c r i n o l . Met., 63, 1262 ( 1 9 8 6 ) . H. S k j o d t . J.A. G a l l a g h e r , J.N. B e r e s f o r d , M. E u c h , J.W. Poser, and R.G.G. R u s s e l l , J. E n d o c r i n o l . , 391 (1985). S. Manolagos, C . Tsoukas, D. P r o u v e d i n i , and B. L a n d g r a f f , J. Bone Min. Res., Suool. 1. A b s t r a c t No. 12. ( 1 9 8 6 ) . T.J: Chambers, J.C. Chambers, J . ' Symonds, and J.A. Darby, J . C l i n . E n d o c r i n o l . Met., 63. 1080 ( 1 9 8 6 ) . G.F. &zuoli, M. P a s s e r i , C. Gennari, S. M i n i s o l a , R . A n t o n e l l i , C . V a l t o r t a , E. .Palunnneri, G.F; C e r v e l l i n , S. G o n n e l l i , and G. F r a n c i n i , C a l c i f . T i s s u e I n t . , 21 3 (1986). H.E. Gruber, J.L. I v e y , D.J. B a y l i n k , M. Matthews, W.N. N e l p , K. Sisorn, and C.H. Chesnut 111, M e t a b o l i s m , 33, 295 ( 1 9 8 4 ) . P. Jaeger. W. Jones, T.L. C l e r n z s , and J.P. H a y s l e t t , J. C l i n . I n v e s t . , 456 (1986).
102,
1,
73,
2,
1,
2,
176 -
S e c t i o n IV-Endocrinology
,
Immunology, M e t a b o l i c D i s o r d e r s
J o h n s , Ed.
T. B u c l i n , J.P. Randin, A.F. Jacquet, M. A z a r i a , M. A t t i n g e r , F. Gomez, P. B u r c k h a r d t , J. Bone Min. Res. 1, Suppl 1, A b s t r a c t No. 347 ( 1 9 8 6 ) . Endicott, M.I. 28. J.C. Stevenson, J.M. Banks, I. M c I n t y r e , R. Hesp, M. Padwick, J.A. Whitehead, J. Bone Min. Res. 1, Suppl. 1, A b s t r a c t No. 277 ( 1 9 8 6 ) . S u p p l . 1, A b s t r a c t H u r l e y , R , D , T i e g s , ana H . Heath 111, J. Bone Min. Res., 29. D.L. No. 447, ( 1 9 8 6 ) . 30. J. Leggate, E. F a r i s h , C.D. F l e t c h e r , W. M c I n t o s h , D.M. H a r t , and J.M. Sommerville, C1 i n . E n d o c r i n o l , 20, 85 ( 1 9 8 4 ) . 31. B. R i i s , K.Thomsen,T. C h r i s t i a n s e n , N. E n g l . J. Med., 316, 173 ( 1 9 8 7 ) . R.P. Heaney, J.C. G a l l a g h e r , C.C. Johnston, R. N e e C A . M. P a r f i t t , B. C h i r , and 32. G.D. Whedon, Am. J. C l i n . N u t r . , 986 (1982). Chesnut 111, and E.J. Teubner, C a l c i f . Tissue 33. J.M. B u r n e l l , D.J. B a y l i n k , C.H. I n t . , 38, 187 ( 1 9 8 6 ) . M a n o v i c , 0. Fontana, C. Tominac, J. Lehmann, and C. Chestnut, J. Bone Min. Res. 34. V. 1, Suppl. 1, A b s t r a c t No. 168 ( 1 9 8 6 ) . 319 ( 1 9 8 6 ) . 35. G.S. Gordan, C. Vaughan, J. N u t r . , 36. F.M. H a l l , M.A. D a v i s , and D.T. Baran, N. E n g l . J . Med., 316, 212 ( 1 9 8 7 ) . M.C. Chapuy, and P.J. Meunier, 37. J.P. Brown. P.D. Delmas, L. M a l a v a l , C. Edouard, L a n c e t , 1, 1094 ( 1 9 8 4 ) . 255, 1600 ( 1 9 8 6 ) . 38. R. Abbasi, G.D. Hodgen, J.A.M.A., C o l l i n s , A. Rim, K. Bowman, and D . V . F o l e y , Am. J . O b s t e t . Gynecol., 39. D . P . (31, ( 1 9 8 4 ) . Stepan, J. P o s p i c h a l , J . P r e s l , and V . Pacovsky, in "Osteoporosis-I: 40. J.J. on Osteoporosis, Proceedings of the Copenhagen International Symposium C . C h r i s t i a n s e n Ed., G l o s t r u p H o s p i t a l , G l o s t r u p , Denmark, 139 ( 1 9 8 4 ) . Sambrook, R.A. 41. J.P. H a r t , M.J. Shearer, L . Klenerman, A. C a t t e r a l l , J. Reeve, P.N. Dodds, L. B i t e n s k y and J. Chayen, J. C l i n . Endocrin.Met., 60, 1268 ( 1 9 8 5 ) . F u j i t a , T. M a t s u i , Y . Nakao, S. Watanabe, M i n e r . E l e c t r o l y t e Metab., 375 42. T. (1984). 43. A.M. P a r f i t t , C a l c i f . T i s s u e I n t . , 2 , S123 ( 1 9 8 4 ) . Baylink, Miner. 44. H . E . Gruber, J.L. I v e y , E . R . Thompson, C.H. Chesnut 111, and D.J. E l e c t r o l y t e Metab., 12, 246 ( 1 9 8 6 ) . 45. P.J. N i j r i e i d e , E . H . B u r g e r , a n d J.H.M. Feyeii, P h y s i o l . Rev., 66, 855, ( 1 9 8 6 ) . G.A. Rodan, T.J. M a r t i n , C a l c i f . T i s s u e I n t . , 33, 349 ( 1 9 8 1 ) . 46. 47. G.L. Wong, J. B i o l . Chem., 259, 4019 ( 1 9 8 4 ) . B.M. Thomson, J. S a k l a t v a l a x n d T.J. Chambers, J . Exp. Med., 104 ( 1 9 8 6 ) . 48. i n "Developments i n C e l l B i o l o g y , 1. S e c r e t o r y Processes", R.T. Dean, P. 49. G. Vaes, S t a h l , Eds, B u t t e r w o r t h s , London, 1985, Chapter 6. 50. M. H o r o w i t z , A. V i g n e r y , R . K . Gershon, and R . Earon, P r o c . N a t l . Acad. S c i . USA, 81, 2181 ( 1 9 8 4 ) . 3544 ( 1 9 8 6 ) . 51. N. Takahashi, G.R. Mundy, and G . D . Roodrnan, J. Immunol 52. K.J. I b b o t s o n , G.D. Roodrnan, L.M. McManus, and G.R. Mundy, J . C e l l B i o l . , 99, 471 (1984). 363 53. R. Baron, L . N e f f , P. T.Van, J.R. N e f u s s i , and A. V i g n e r y , Am. J. P a t h o l . , (1986). Kahn, E . C . Crouch, J . J . J e f f r e y , and S.L. Teitelbaurn, J . C e l l B l a i r , A.J. 54. H.C. Biol., 1164 ( 1 9 8 6 ) . 55. T.J. Chambers, P.M.J. McSheehy, B . M . Thomson, and K . F u l l e r , E n d o c r i n o l o g y , 234 (1985). 56. R.L. J i l k a , Bone, 7, 29 ( 1 9 8 6 ) . 57. S. Mohan, T. L i n k h a r t , J . F a r l e y , and D. B a y l i n k , C a l c i f . T i s s u e I n t . , 2 , 5139 (1984). 58. E . C a n a l i s , C l i n . Orthop., 193, 246 ( 1 9 8 5 ) . I a f r a t i , S.E. Doleman, and M. K l a q s b r u n , J . 59. P.V. Hauschka, A.E. M a v r a k o x M.D. B i o l . Chem., 261, 12665 ( 1 9 8 5 ) . 60. W.A. Soskolne, Z . Schwartz, and A. Ornoy, Bone, 7 , 4 1 ( 1 9 8 6 ) . 61. J.N.M. Heersche, C l i n . I n v e s t . Med., 5, 173 ( 1 9 8 7 ) . Jerome, D.B. Kimmel, J.A. M c A l i s t e r , and D.S. Weaver, C a l c i f . T i s s u e I n t . , 62. C . P . 206 ( 1 9 8 6 ) . K o r i t n i k , C a l c i f . Tissue Int., 63. L.C. M i l l e r , D . S . Weaver, J.A. M c A l i s t e r , and D.R. 38, 62 ( 1 9 8 6 ) . Faugere, M. Rush, R.M. F r i e d l e r , and H . H . M a l l u c h e , J . Bone Min. Res., 64. M.C. Suppl. 1, A b s t r a c t No. 303 ( 1 9 8 6 ) . 65. R.T. T u r n e r , N.H. B e l l , J. Bone Min. Res., 399 ( 1 9 8 6 ) . 66. 0.0. Thompson, G.A. Rodan, J. Bone Min. Res., 1, Suppl. 1, A b s t r a c t No. 96 ( 1 9 8 6 ) . Ignaszewski, C a l c i f . Tissue I n t . , 67. T.J. Wronski, PL.L. Lowry, C . C . Walsh, and L.A, 37, 324 ( 1 9 8 5 ) . 68. KH. Reddi i n "Bone and M i n e r a l Research, Annual 3," W.A. Peck, Ed., E l s e v i e r , Amsterdam, 1985, D . 27. S.K. N i s h i m o t o , C'.H. Chang, E. Gendler, W.F. S t r y k e r , and M.E. Nimni, C a l c i f . 69. 617 ( 1 9 8 5 ) . Tissue I n t . ,
27.
1,
.
36,
116,
149,
lo,
164,
., 137,
122,
102,
116,
2,
1,
1,
37,
Chap, 17 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107, 108. 109. 110. 111. 112. 113. 114. 115.
Bone Metabolism a n d Osteoporosis
Hayward, Caggiano
M. M a t s u s h i t a , T. Tsuboyama, R. Kasai, H. Okumura, T. Yamamuro, K. H i g u c h i , K. H i g u c h i , A. Kohno, T. Yonezu, A. U t a n i . M. Umezawa, and T. Takeda, Am. J. P a t h o l . , 125, 276 (1986). C. C. Johnston, Jr. and S. E p s t e i n i n " E n d o c r i n o l o g y o f Calcium Metabolism," J.A. Parons, Ed., Raven Press, New York, 1982, p. 467. B. Lund, J.G. Pedersen, C. Egsmore, B. Lund, Adv. Exp. Med. B i o l . , 149 (1984). V.J. H a j i r o u s s o u , and M. Webley, Ann. Rheum. D i s . , 43, 24 (1984). P;N. Sambrook, J.A. Eisman, M.G. Yeates, N.A. POCOCK S. E b e r l , and G.D. Champion, Ann. Rheum. D i s . , 45, 950 (1986). D.N. Kalu, R.R. H a a i n , and R. Cockerham, Age, 6, 114 (1983). C.H. Chesnut 111, J.L. I v e y , H.E. Gruber,-M. Matthews, W.B. Nelp, K. Sisom, and O.J. B a y l i n k , Metabolism, 32, 571 (1983). C. Tabuchi, D.J. Simmons, Fausto, J.E. R u s s e l l , I . Binderman, and L.V. A v i o l i , J. Clin. I n v e s t . , 637 (1986). C . Tabuchi, D.J. Simmons, A. Fausto, I . R . Reid, J.E. R u s s e l l , I. Binderman, and L.V. A v i o l i , J. Bone Min. Res. Suppl. 1, A b s t r a c t No. 98, (1986). H. F l e i s c h , "Bone and M i n e r a l Research, Annual l", W.A. Peck, Ed.; E x c e r p t a Medica, ( E l s e v i e r ) : Amsterdam , (1983); p. 319. H. Shinoda, G. Adamek, R. F e l i x , H. F l e i s c h , R. Schenk, and P. Hagan, C a l c i f . T i s s u e I n t . , 35, 87 (1983). D.J. Rowe a n d 7 . J . Hays, Metab. Bone Ois. & Rel. Res. 5 , 13 (1983). D.J. Rowe, Bone, 6, 433 (1985). P. H. Stevenson and J.R. Stevenson, C a l c i f . T i s s u e I n t . , 38, 227 (1986). J.M. D e l a i s s e . Y. Eeckhout, and G. Vaes, L i f e S c i . , 37, 2 3 1 (1985). K. Hoekman, S:E. Papapoulos, A.C.B. P e t e r s , 0.L.M; B i j o v e t , J. C1 n. E n d o c r i n o l . Metab., 61, 952 ( 1 9 8 5 ) . G.R. Snow, and C. Anderson. C a l c i f . T i s s u e I n t . . 38. 217 (1986). J.A. Kanis, and P.J. Meunier, Q. J. Med., New S e r z s L I I I ; 210; 145 ( 984). G . R . I . Power and J.D.L. Gay, C l i n . I n v e s t . Med., 9, 4 1 ( 1 9 8 n R. Lappalainen, M. K n u u t t i l a , S. Lammi, and ETM. Alhava, J. Chron c Dis., 36, 707 '( 1983). L.G. Strause, J.Y. R e g i n s t e r , P . Franchimont, and P. Saltman, J. Bone Min. Res. Suool. 1. A b s t r a c t 234 ( 1 9 8 6 ) . r J.R. W. Lau, and D.J. B a y l i n k , C a l c i f . T i s s u e I n t . , 40, F a r l e y , N.M. Tarbaux,'K.-H. 35 (1987). A.D. Kenny, C a l c i f . T i s s u e I n t . , 37, 126 ( 1 9 8 5 ) . W.S. Sly, D. Hewett-Emmett, M.P. Whyte, Y . - S . L. Yu, and R.E. Tashian, Proc. N a t l . Acad. S c i . USA, 80, 2752 ( 1 9 8 3 ) . C . V . Gay, W.J. M z l l e r , Science, 183, 432 (1974). H. Cao and C . V . Gay, E x p e r i e n t i a , x , 1472 ( 1 9 8 5 ) . R.E. Anderson, W.S.S. Jee, and O.M. Woodbury, C a l c i f . T i s s u e I n t . , 646 (1985). G.E. H a l l , and A.D. Kenny, C a l c i f . T i s s u e I n t . , 37, 134 (1985). G.E. H a l l , and A.D. Kenny, Pharmacology, 30, 3 3 9 7 1 9 8 5 1 . H.A. Simmons, L.G. Raisz, W.J. Thompson, P.S. Anderson, and G.A. Rodan, J. Bone Min. Res. 1., S U D D ~ . 1. A b s t r a c t 86 (1986). C.T. Stier; Jr., and H.D. I t s k o v i t z , Annu. Rev. Pharmacol. T o x i c o l , 3,101 ( 1 9 8 6 ) . C.M. P r o u d f i t , J.A.M.A., 252, (1984). R.O. Wasnich, R.J. B e n f a n K K. Yano, L. H e i l b r u n , and J.M. Vogel, N. E n g l . J. Med., 309, 344 ( 1 9 8 3 ) , R.D. Washnick, P.D. Ross, L.K H e i l b r u n . J.M. Voqel, K. Yano, and R.J. Benfante, O b s t e t . Gynecol., 67, 457 (1986). P.J. D r i n k a , and W T. N o l t e n , J. Am. G e r i a t r . SOC., 32, 405 ( 1 9 8 4 ) . K. Sakhaee, M.J. N i c a r , K. Glass, J.E. Z e r w e k K and C.Y.C. Pak, J . Clin. E n d o c r i n o l . Met., 59, 1037 ( 1 9 8 4 ) . R . Baron, L. N e f f , T . Roy, A. B o i s v e r t , and M. Caplan, C e l l , 46, 311 (1986). R.E. Anderson, O.M. Woodbury, and W.S.S. Jee, C a l c i f . T i s s u e Et., 2, 252 ( 1 9 8 6 ) . T. Akisaka, and C.V. Gay, C e l l T i s s u e Res., 57 (1986). J. Tuukkanen, H.K. Vaananen, C a l c i f . T i s s u e I n t . , 38, 123 (1986). J.K. Heath, S.J. A t k i n s o n , M.C. M e i k l e , and J.J,Reynolds, Biochim. Biophys. Acta, 802, 151 (1984). K. Otsuka, J. Sodek, and H. Limeback, Eur. J. Biochem., 145, 123 (1984). T.J. Chambers, and K. F u l l e r , J. C e l l S c i . , 76, 155 ( 1 9 8 r L.G. R a i s z and TJ. M a r t i n .in "Bone and M i n e r 5 Research, Annual 2," W.A. Peck, Ed., E l s e v i e r , Amsterdam, 1984, p. 286. 0. Hoffmann, K. K l a u s h o f e r , K. K o l l e r , and M. P e t e r l i k , P r o s t a g l a n d i n s , 30, 857 ( 1985). R.C. W i l l i a m s , M.K. J e f f c o a t , M.L. Kaplan, P. Goldhaber, H.G. Johnson, and W.J. Wechter. Science. 640 (1985)
171,
78,
1,
1,
-7
2,
. r
9,
227,
178
S e c t i o n IV-Endocrinology, Immunology, M e t a b o l i c D i s o r d e r s
J o h n s , Ed.
116. W . Lloyd, V.S. Fang, H. Wells, and A.H. Tashjian, Jr., Endocrinology, 85, 763 (1969). 163 ( 1 9 7 1 ) . 117. V.S. Fang. C. Minkin, P. Goldhaber, Science, 118. J.C. Robin, S.D. Sharma, K. Francis, M. Rosenstein, R. Moore, J.A. Vida, C.C. Thomas, Jr., and J.L. Ambrus, J. Med., 11, 1 5 (1980). 119. L.G. Raisz. C. Alander, C. OnkelinxTand G.A. Rodan, Calcif. Tissue Int., 37, 556 ( 1985). 120. J.C. Robin, M.J. Brown, N. Weinfeld, R.M. Dziak. Calcif. Tissue Int., 2 , 194 ( 1984). 121. S.Y. Ly, C . Rebut-Bonneton, and L. Miravet, Horm. Metab. Res., 152 (1985). 122. G. Eilon, and L.G. Raisz, Calcif. Tissue Int., 34, 506 (1982). 123. U. Lerner, and G. Granstrom, Eur. J. Pharmacol., 105, 1 ( 1 9 8 4 ) . 124. U . Lerner, and G.T. Gustafson, Experientia, 35, 5 F ( 1 9 7 9 ) . 125. M.T. Garba, and P.J. Marie, Calcif. Tissue Iz.,38, 296 ( 1 9 8 6 ) . 126. T. Komoda, E . Ikeda, Y . Nakatani, Y. Sakagishi, N. Maeda, T. Kato, and M. Kumegawa, Biochern. Pharmacol., 34, 3885 (1985). 127. P. Goldhaber, and L. Ebadjija, Proc. SOC. Exp. Biol. Med., 169, 105 ( 1 9 8 2 ) . 128. M.L. Tyan, Proc. SOC. Exp. Biol. Med., 179, 240 ( 1 9 8 5 ) . 129. G.A. Roden, L.A. Bourret, A. Harvey, a n m . Mensi, Science, 189, 467 ( 1 9 7 5 ) . 130. N.S. Krieger, T.S S t a p p p n h e c k , and P.H. Stern, J. Clin. I n v e x , 79, 444 (1987) 131. N.S. Krieger, V.M. Stathopoulos, and P.H. Stern, Circulation, 59 ( 1 9 8 6 ) . 132. J.C. Robin, and J.L. Ambrus, J. Med., 14, 137 ( 1 9 8 3 ) . 133. J.C. Robin, J.L. Ambrus, J. Med., 15, 519 ( 1 9 8 4 ) . 134. J.C. Robin, and J.L. Ambrus, J. M e x , 13, 465 ( 1 9 8 2 ) . 135. I . Yamazaki, and M. Kinoshita, Life S c r , 2 , 1535 ( 1 9 8 6 ) . 136. I . Yamazaki, A. Shino, Y . Shimizu, R. Tsukuda, Y . Shirakawa, and M. Kinoshita, Life Sci., 2 , 951 ( 1 9 8 6 ) . 137. R.P. Warrell, Jr., R.S. Bockman, C.J. Coonley, M. Isaacs, and H. Staszewski, J. Clin. Invest., 73, I487 ( 1 9 8 4 ) . 138. R.P. Warrell, J C , U S Patent 4,529,593, 1985.
172,
17,
z,-m,