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Effects of corticosteroids on bone turnover
Respiratory Medicine (1993) 87 (Supplement A), 15-21
Effects of corticosteroids on bone turnover D. J. HOSKING
City Hospital, Hucknall Road, Nottingham NG5 1PB, U.K.
The pathophysiology ofcorticosteroid-induced osteoporosis is complex, but centres around a primary inhibition of osteoblastic activity compounded by the effects of secondary hyperparathyroidism. The preservation of the microanatomy of bone in the early stages of the disease, coupled with strategies to prevent the emergence of secondary hyperparathyroidism, and the potential availability of osteoblastic stimulants offer the hope of minimizing this important side-effect of corticosteroid therapy. Introduction
The mechanisms by which corticosteroids lead to a reduction in bone mass are complex and involve both direct and indirect effects on the remodelling cycle (Fig. 1). Extracellular calcium homoeostasis is perturbed by a reduction in intestinal calcium absorption and renal tubular calcium reabsorption, leading to the development of secondary hyperparathyroidism. There are also effects on the pituitary gonadal and pituitary adrenal axes, which potentiate the effects of parathyroid hormone (PTH) on bone. The major effects of corticosteroids, however, are on the bone remodelling cycle, acting to inhibit osteoblastic activity and to shift the calcium balance into a negative phase.
Calcium Homoeostasis
There is general agreement that the supraphysiological doses of oral corticosteroids which are used
in clinical medicine decrease intestinal calcium absorption and renal tubular reabsorption, leading to a negative calcium balance (1). INTESTINALCALCIUMABSORPTION The mechanisms by which net calcium transport is reduced by corticosteroids are complex and their elucidation is bedevilled by the practical problems of making physiologically relevant measurements. The result is that the data from many studies appear to conflict with each other. The effects on the intestine appear to be nonuniform, with decreased absorption in the duodenum (2), where transport is normally most active, but with generally increased absorption in the colon (3). The decline in calcium absorption seems independent of changes in circulating 1,25-dihydroxycalciferol [1,25(OH)2D ], which may increase in the early stages of corticosteroid therapy (4) (due to the development of secondary hyperparathyroidism) at the same time as absorption is declining. Intestinal and bone receptors
Supraphysiological doses of corticosteroid
,kBone formation /.f
1'Bone resorption ~ ~'Remodelling units ,4
4,Calcium abso~,on
4,Renal calcium reabsorption
\ ~,Sex hormone ,kPlasmacalcium secretion ;" ~'Parathyroid hormone secretion
Fig. 1 Pathogenesis of corticosteroid-inducedosteoporosis. 0954-6111/93/0A0015+ 07 $08.00/0
9 1993Bailli6reTindall
16 D. J. Hosking for 1,25(OH)2D are increased by corticosteroids (5), but this apparent paradox may be explained by increased catabolism of membrane-bound 1,25(OH)zD (6). Levels of the calcium-binding protein, which is 1,25(OH)2D-dependent , also decrease (7), though the way that this translates into a reduction in calcium absorption is uncertain. Although calcium uptake by membrane-bound vesicles appears unaffected by corticosteroids (8), there is enhanced N ~ K ATPase activity in the basolateral membrane of the mucosal cell (9). This may indirectly increase the back diffusion of calcium through the intercellular space between enterocytes into the intestinal lumen, due to the increased hydrostatic pressure consequent on an enhanced rate of flow of sodium and water towards the serosal surface. Dose is clearly an important consideration, and in animal experiments the decline in calcium absorption is dose dependent (10). This may reflect the result of a dose dependent increase in transcellular calcium flux, accompanied by an even larger exponential rise in calcium secretion back into the lumen so that net transport declines (11). Finally, there is the problem that the intestine adapts slowly to changes in dietary constituents (12), and many studies have not been performed under steady-state conditions. Net calcium absorption in corticosteroid-treated animals declines further with high sodium, low calcium diets (13,14), and this might be an important phenomenon in man. The problem is that the relative magnitude of these different effects is uncertain, which makes preventative measures more difficult to,identify in the clinical situation. R E N A L T U B U L A R R E A B S O R P T I O N OF C A L C I U M
Urinary calcium excretion increases at the start of corticosteroid therapy (15) and, together with the decline in intestinal calcium absorption, leads to the development of a negative calcium balance and secondary hyperparathyroidism. However, calcium excretion may not be increased in the long term (16), and it is often difficult in the clinical setting to separate changes due to an increased filtered load of calcium from those due to decreased tubular reabsorption. This is well illustrated by the reports of an increase in fasting calcium excretion during chronic corticosteroid therapy (17). While this might be due to a reduction in renal tubular reabsorption (18), it could also reflect an increased filtered calcium load from a net increase in bone resorption or the vasodilatory effect of corticosteroids increasing renal blood flow and glomerular filtration rate (19). There are also the problems of separating direct effects of corticosteroids on renal cells from those due
to secondary events, such as changes in PTH secretion, sodium excretion, or concomitant thiazide therapy. However, there are potential mechanisms by which corticosteroids could exert a direct renal effect. The kidney has classic glucocorticoid receptors (20), and renal cells contain vitamin-D-dependent calciumbinding proteins, which may be similar or identical to those in the gut (21) and may be equally impaired by corticosteroid therapy. SEX H O R M O N E P R O D U C T I O N
Sex hormones are potent regulators of the bone remodelling cycle, but their production may be reduced by corticosteroids through actions on the pituitary, gonad, or adrenal glands. In the pituitary, corticosteroids blunt the luteinizing hormone response to luteinizing hormone releasing hormone (22,23), thereby reducing gonadal production of oestrogens or testosterone. There is also clinical and experimental evidence for a direct end organ effect, as shown by the inhibition of follicle-stimulating-hormone-mediated oestrogen production by cultured granulosa cells (24) or Leydig cells (25). This effect may be mediated by a decrease in the number ofgonadotrophin-binding sites in the testes (26) or ovary. Corticosteroids also inhibit adrenocorticotrophin secretion, which in turn reduces the adrenal production of androstenedione. This may be of particular importance in postmenopausal women treated with corticosteroids, since the peripheral conversion in adipose tissue of androstenedione to oestrone is the principal source of oestrogens (27), even though it binds weakly to the oestradiol receptor on osteoblasts (28). The reduction in sex hormone production appears to have an additive effect with the increased secretion of PTH (29) and results in a shifting of the bone remodelling cycle into a persistently negative phase and makes a significant contribution to the development of osteoporosis. Understanding the mechanisms by which this occurs requires a more detailed consideration of the bone remodelling cycle.
Bone Remodelling It is fundamental to the maintenance of skeletal integrity that bone resorption and formation are coupled both temporally and quantitatively. The major effect of corticosteroids appears to be depression of osteoblastic function (Fig. 2). This can be demonstrated histomorphometrically as a reduction in mean wall thickness, lamella thickness, osteoid surface, and osteoid seam width (30). Biochemical markers of osteoblastic activity, such as osteocalcin,
Effects o f corticosteroids on bone turnover I I I
Boneloss 35%
I
4
17
Resorption > Formation Normal bone modelling unit birth rate
I
Months
I
Bone loss 43%
I _
Resorption > Formation Increased bone modelling unit birth rate
_
I__
Months
Fig. 2 Relative contributions of uncoupling of bone remodelling and birth rate of bone modelling units to production of bone loss. are also depressed (31), though they recover when, for example, bone formation increases following the successful treatment of Cushing's syndrome (32). Tissue culture experiments are in broad agreement with the clinical findings, but suggest that the effects on osteoblasts are biphasic. During the first 24 h of culture, collagen synthesis by osteoblasts is stimulated, but subsequently declines (33). The mechanism of action is believed to be through specific cytoplasmic glucocorticold receptors on osteoblasts whose activation leads to inhibition of both replication and differentiation (34,35). Osteoblasts also have a shortened life span (36), which would be consistent with changes that indicate a reduction in bone formation rate, such as the reduced mean wall thickness. Bone resorption is more difficult to assess from static histomorphometric parameters. Although resorption surfaces are increased, osteoclasts are not abundant, and this appearance could be a result of delayed infilling due to reduced bone formation rather than increased osteoclastic activity (30). Biochemical markers of bone resorption, such as hydroxyproline, increase in the early stages of corticosteroid therapy (37) but fall back to baseline values with long-term treatment (38). In this respect the findings are consistent with the temporal changes in fasting calcium excretion (15,16), The data that are available, however, are consistent in pointing to an uncoupling of
bone formation and resorption by corticosteroids leading to net bone loss. The other factor that needs consideration at this point is the role of secondary hyperparathyroidism caused by the reduction in intestinal calcium absorption and renal reabsorption. The rise in PTH seems to exacerbate the problem due to the imbalance between bone formation and resorption (39), but is not itself a primary factor. This view is supported by bone mineral density measurements in mild asymptomatic hyperparathyroidism, which show a selective reduction in cortical bone but a relative preservation of trabecular bone (40,41). It has even been suggested that hyperparathyroidism protects against age-related loss of trabecular number (42). In corticosteroid-treated patients, however, there is an additional dimension in that there is already a net loss of bone with each remodelling cycle. Since PTH increases the birth of new remodelling units, the effect of secondary hyperparathyroidism will be to amplify this uncoupling and increase the amount of bone lost per unit time (43) (Fig. 2). It may be for this reason, rather than because of any increase in bone resorption, that the combination of corticosteroid therapy and secondary hyperparathyroidism has such a deleterious effect on the skeleton. Corticosteroid-induced osteoporosis also differs from idiopathic osteoporosis in terms of the micro-
18
D. J. Hosking Corticosteroids + secondary hyperparathyroidism
Corticosteroids + control of secondary hyperparathyroidism
:
Transient gain of bone
Bone loss
I I ]
r--[
i__J F>R
Resorption>>Formation ?Bone modelling unit birth rate
I
I__
R>F l__ Normal bone modelling unit birth rate
Months Corticosteroids + secondary : Corticosteroids + secondary hyperparathyroidism ', hyperparathyroidism + osteoblast stimulant _t_
84
1__
loss
__1
[__
I
I
[__]
Resorption>>Formation "['Bone modelling unit birth rate
Sustained gain of bone
I
Formation>Resorption ?Bone modelling unit birth rate y
Months Corticosteroids + secondary hyperparathyroidism .
.
.
.
.
.
.
.
i Corticosteroids + osteoblast stimulant ,, + control of secondary hyperparathyroidism i .
.
.
.
.
.
.
.
.
.
.
Bone loss
--l_
l_
Resorption>>Formation ?Bone modelling unit birth rate
l
.
.
.
[
.
I
Sustained gain of bone
__J-I
] Formation>>Resorption Normal bone modelling unit birth rate
Months
Fig. 3 Therapeutic strategies for correction of corticosteroid-inducedosteoporosis. anatomical appearance (30). In corticosteroid-induced osteoporosis, the number of trabeculae and their surface area are relatively preserved, though individual plates are very thin (trabecular attenuation). In idiopathic osteoporosis, the major driving force to bone loss is osteoclastic resorption. Trabecular width is relatively preserved in this situation, but the lamellae are perforated by resorption, with a loss of trabecular surface and continuity. This difference has important implications for treatment, as the preservation of the thinned microanatomical structure provides the foundation on
which new bone could be deposited with restoration of mechanical integrity, only providing that bone formation could be appropriately stimulated. Plans for the treatment of established osteoporosis, however, must also take into account the role of parathyroid overactivity (Fig. 3). Although it is a contributory factor to the development of osteoporosis, it could also be harnessed to restore bone mass more quickly using stimulators of bone formation (43). If bone formation could be stimulated so that formation can exceed resorption, then the net gain of bone would be proportional to the number of osteo-
Effects o f corticosteroids on bone turnover
blasts. Since the b i r t h rate of new remodelling units is increased by P T H , this would have a favourable influence on the restoration o f b o n e mass. A l t h o u g h inhibitors o f bone resorption could lead to a n excess o f f o r m a t i o n over resorption, since the latter is already depressed by corticosteroids, the rate o f increase in b o n e would be m u c h slower t h a n with an osteoblast stimulator. It has to be emphasized, however, t h a t strategies for the prevention of corticosteroid-induced osteoporosis include measures to reduce the emergence of secondary h y p e r p a r a t h y r o i d i s m (35,44). These include m a i n tenance o f a n a d e q u a t e calcium a n d vitamin D intake, avoidance of hypercalciuria by the use of low sodium diets or thiazide diuretics, a n d the t r e a t m e n t of early evidence of hypogonadisrn. These measures need to be coupled with policies to achieve disease control with the smallest dose of a b s o r b e d corticosteroid, as well as m a i n t e n a n c e o f osteoblastic function t h r o u g h physical activity a n d the avoidance of other inhibitors, such as alcohol excess.
References
1. Nordin BEC, Marshall DH, Francis RM, Crilly RG. The effects of sex steroid and corticosteroid hormones on bone. JSteroidBiochem 1981; 15:171 174. 2. Kimberg DV, Baerg RD, Gershon E, Graudusius RT. Effect of cortisone treatment on the active transport of calcium by the small intestine. J Clin Invest 1971; 50: 1039-1044. 3. Lee DB. Unanticipated stimulatory action of glucocorticoids on epithelial calcium absorption. Effect of dexamethasone on rat distal colon. J Clin Invest 1983" 71: 322-328. 4. Hahn T J, Halstead LR, Bran DT. Effects of short term glucocorticoid administration on intestinal calcium absorption and circulating vitamin D metabolite concentration in man. J Clin Endocrinol Metab 1981; 52: 111 115. 5. K orkor AB, Kuchibotla J, Arrieh M, Gray RW, Gleason WA Jr. The effects of chronic prednisolone administration on intestinal receptors for 1,25-dihydroxyvitamin D 3in the dog. Endocrinology 1985; 117:2267 2273. 6. Carte M, Ayigbede O, Miravet L, Rasmussen H. The effect ofprednisolone upon the metabolism and action of 25-hydroxy and 1,25-dihydroxyvitamin D,. Proc Natl AcadSci USA 1974; 1: 299(~3000. 7. Feher J J, Wasserman RH. Intestinal calcium binding protein and calcium absorption in cortisol treated chicks: effects of vitamin D 3 and 1,25-dihydroxyvitamin D 3. Endocrinology 1979; 104:547-551. 8. Shultz TD, Bollman S, Kumar R. Decreased intestinal calcium absorption in vivo and abnormal brush border membrane vesicle calcium uptake in cortisol-treated chickens: evidence for dissociation of calcium absorption from brush border vesicle uptake. Proc Natl Acad Sci USA 1982; 79:3542 3546. m
~
19
9. Charney AN, Kinsey MD, Myers L, Gianella RA, Gotts RE. Na + K* activated adenosine triphosphatase and intestinal electrolyte transport. Effect of adrenal steroids. J Clin Invest 1975; 56" 653-660. 10. Gennari C, Bernini M, Nardi P et al. Glucocorticoids: radiocalcium and radiophosphate absorption in man. In: Dixon AStJ, Russell RGG, Stamp TCB, eds. Osteoporosis, a multidisciplinary problem. London: Royal Society of Medicine, 1983: 75-80. 11. Ferretti J, Bazan JL, Alloatti D, Puche RC. The intestinal handling of calcium by the rat in vivo, as affected by cortisol. Effect of dietary calcium supplements. Calcif Tissue Res 1978; 25:1 6. 12. Malm OJ. Calcium requirements and adaptation in adult man. ScandJ Clin Lab Invest 1958; 10 (suppl. 36). 13. Adams JS, Wahl TO, Lukert BP. Effects of hydrochlorothiazide and dietary sodium restriction on calcium metabolism in corticosteroid treated patients. Metabolism 1981; 30:217 221. 14. Lukert BP, Stanbury SW, Mawer EB. Vitamin D and intestinal transport of calcium: effects of prednisolone. Endocrinology 1973; 93: 718-722. 15. Hahn TJ, Halstead LR, Strates B, Imbimbo B, Baran DT. Comparison of subacute effects of oxazacort and prednisolone on mineral metabolism in man. Calcif Tissue lnt f980; 31:10~115. 16. Hahn TJ, Halstead LR, Teitelbaum SL, Hahn BH. Altered mineral metabolism in glucocorticoid induced osteopenia. J Clin Invest 1979; 64:655 665. 17. Suzuki Y, Ichikawa Y, Saito E, Homma M. Importance of increased urinary calcium excretion in the development of secondary hyperparathyroidism of patients under glucocorticoid therapy. Metabolism 1983; 32: 151-156. 18. Reid IR, Ibbertson HK. Evidence for decreased tubular reabsorption of calcium in glucocorticoid treated asthmatics. Hormone Res 1987; 27: 200-204. 19. Field M J, Giebisch GH. Hormonal control of renal potassium excretion. Kidney lnt 1985; 27: 379-387. 20. Fuller PL, Funder JW. Mineralocorticoid and glucocorticoid receptors in human kidney. Kidney Int 1976; 10: 154-157. 21. Delorme AC, Danan JL, Mathieu H. Biochemical evidence for the presence of two vitamin D dependent calcium-binding proteins in mouse kidney. J Biochem Chem 1983; 258: 1878--1884. 22. Sakakura M, Takebe K, Nakagowa S. Inhibition of luteinizing hormone secretion induced by synthetic LRH by long term treatment with glucocorticoids in human subjects. J Clin Endoerinol Metab 1975; 40: 774-779. 23. Luton JP, Thieblot P, Valcke JC, Mahoudeau JA, Bricaire H. Reversible gonadotropin deficiency in male Cushing's disease. J Clin Endocrinol Metab 1977; 45: 488~495. 24. Hsueh AJ, Erickson GF. Glucocorticoid inhibition of ESH induced oestrogen production in cultured rat granulosa cells. Steroids 1978; 32:639 648. 25. Schaison G, Durand F, Mowszowicz I. Effect of glucocorticoids on plasma testosterone in man. Acta Endocrinol ( Copenh ) 1978; 89:126~131. 26. Saez JM, Morera AM, Haour F, Evain D. Effect of in vivo administration ofdexamethasone, corticotropin and human chorionic gonadotrophin in steroidogenesis and protein and DNA synthesis of testicular interstitial cells in prepubertal rats. Endocrinology 1977; 101: 12561263.
20
D . J. H o s k i n g
27. Crilly RG, Cawood M, Marshall DH, Nordin BEC. Hormonal status in normal, osteoporotic and corticosteroid treated post menopausal women. J R Soc M e d 1978; 71: 733-736. 28. Goulding A, Gold E. Effects of chronic prednisolone treatment on bone resorption and bone composition in intact and ovariectomized rats and in ovariectomized rats receiving fl-estradiol. Endocrinology 1988; 122: 482487. 29. Eriksen EF, Coluard DS, Berg NJ et al. Evidence of estrogen receptors in normal human osteoblast like cells. Science 1988; 241: 84~86. 30. Aaron JE, Francis RM, Peacock M, Makins NB. Contrasting microanatomy of idiopathic and corticosteroid induced osteoporosis. Clin Orthop Rel Res 1989; 243: 294 305. 31. Reid IR, Chapman GE, Fraser TR et al. Low serum osteocalcin levels in glucocorticoids-treated asthmatics. J Clin EndocrinolMetab 1986; 62:379 383. 32. Pocock NA, Eisman JA, Dunstan CR, Evans RA, Thomas DH, Huq NL. Recovery from steroid induced osteoporosis. Ann Intern M e d 1987; 107:319 323. 33. Canalis EM. Effect of glucocorticoids on type I collagensynthesis, alkaline phosphatase activity, and deoxyribonucleic acid content in cultured rat calvariae. Endocrinology 1983; 112: 931439. 34. Feldman D, Dziak R, Koehler R, Stern P. Cytoplasmic glucocorticoid binding proteins in bone cells. Endocrinology 1975; 96: 29-36. 35. Lukert BP, Raisz LG. Glucocorticosteroid-induced osteoporosis: pathogenesis and management. Ann Intern M e d 1990; 112:352 364. 36. Dempster DW, Arlott MA, Meunier PJ. Mean wall thickness and formation periods of trabecular bone packets in corticosteroid-induced osteoporosis. Calcif Tissue lnt 1983; 35: 410~17. 37. Gennari C, Imbimbo B, Montagnani M, Bernini M, Nardi P, Avioli LV. Effects ofprednisolone and deflazacort on mineral metabolism and parathyroid hormone activity in humans. CalcifTissue Int 1984; 36:245 252. 38. Need AG, Hartley TF, Philcox JC, Nordin BEC. Calcium metabolism and osteoporosis in corticosteroidtreated postmenopausal women. Aust N Z J M e d 1986; 16:341 346. 39. Dempster DW. Bone histomorphometry in glucocorticoids induced osteoporosis. J Bone Miner Res ! 989; 4: 137 141. 40. Silverberg SJ, Shane E, De La Cruz L et al. Skeletal disease in primary hyperparathyroidism. J Bone Miner Res 1989; 4: 283-291. 41. Parisien M, Silverberg SJ, Shane E et al. The histomorphometry of bone in primary hyperparathyroidism: preservation of cancellous bone structure. J Clin Endocrinol Metab 1990; 70: 93(~938. 42. Bilezikien JP, Silverberg SJ, Shane E, Parisien M, Dempster DW. Characterisation and evaluation of asymptomatic primary hyperparathyroidism. J Bone Miner Res 199l; 6 (suppl 2.): 585 589. 43. Jee WSS, Clark I. Glucocorticoid induced osteoporosis. In: De Luca HF, Frost HM, Jee WSS, Johnston CC, Parfitt AM, eds. Osteoporosis. Recent advances in pathogenesis and treatment. Baltimore: University Park Press, 1981:331 342. 44. Reid IR. Pathogenesis and treatment of steroid osteoporosis. Clin Endocrino11989; 30: 83-103.
Discussion
R. Eastell Parathyroid hormone (PTH) is central to all your models of the effects of corticosteroids on bone turnover. However, the literature in this field is not all in agreement and there has been a suggestion that there is an increase in P T H sensitivity rather than an increase in the level of PTH. D. Hosking The model I have proposed is not dependent on secondary hyperparathyroidism for bone uncoupling. Secondary hyperparathyroidism increases the severity of osteoporosis. It is certainly true that a model which depends on osteoblast suppression does not depend on an increase in P T H ; increased P T H simply increases the severity of the disease. G. Boyd Is it true that fully developed osteoporosis in postmenopausal women is often associated with secondary hyperparathyroidism, and that this model can be used to investigate the potential problems of corticosteroid treatment in asthmatics? D. Hosking Possibly; the attraction of this model is that it is potentially reversible. However, corticosteroid-induced osteoporosis is, I think, different from postmenopausal osteoporosis because the microarchitecture of the bones is not the same in these two diseases. There is good evidence that in corticosteroidinduced osteoporosis, the osteoblasts are suppressed, whereas in postmenopausal osteoporosis, osteoclastic resorption increases the destruction of trabeculae. The key point is that, although not essential for the development of osteoporosis, P T H increases its severity. P T H does not have a primary effect of its own on the development of osteoporosis. N. Barnes If the problem is suppression of osteoblasts and you discontinue oral corticosteroid therapy before major damage is effected, how long does it take for the osteoblasts to begin behaving normally? Can the osteoblasts undo the damage and remodel the bone that has been lost? D. Hosking l think there is evidence of recovery from corticosteroid-induced osteoporosis. If Cushing's syndrome is treated, there is an increase in osteocalcin within a few weeks and bone mineral density increases. That is why the preservation of the microarchitecture is so important. If the microarchitecture is in place, it is possible to restore bone function as well as mass. If the microarchitecture is lost, making the small pieces of bone bigger does not increase the mechanical integrity.
Effects o f corticosteroids on bone turnover N. Barnes But is there evidence that you do get increases in bone mass when corticosteroid treatment is discontinued? Does the bone density return to normal? D. Hosking No, the bone mass does not return completely to normal, though some recovery does occur.
21
N. Barnes Is there evidence that fluoride would be particularly useful in corticosteroid-induced osteoporosis? D. Reid I think many people would say that there is, because the histomorphology data show restoration to normal levels.
Effects of corticosteroids on bone turnover D. J. HOSKING
City Hospital, Hucknall Road, Nottingham NG5 1PB, U.K.
The pathophysiology ofcorticosteroid-induced osteoporosis is complex, but centres around a primary inhibition of osteoblastic activity compounded by the effects of secondary hyperparathyroidism. The preservation of the microanatomy of bone in the early stages of the disease, coupled with strategies to prevent the emergence of secondary hyperparathyroidism, and the potential availability of osteoblastic stimulants offer the hope of minimizing this important side-effect of corticosteroid therapy. Introduction
The mechanisms by which corticosteroids lead to a reduction in bone mass are complex and involve both direct and indirect effects on the remodelling cycle (Fig. 1). Extracellular calcium homoeostasis is perturbed by a reduction in intestinal calcium absorption and renal tubular calcium reabsorption, leading to the development of secondary hyperparathyroidism. There are also effects on the pituitary gonadal and pituitary adrenal axes, which potentiate the effects of parathyroid hormone (PTH) on bone. The major effects of corticosteroids, however, are on the bone remodelling cycle, acting to inhibit osteoblastic activity and to shift the calcium balance into a negative phase.
Calcium Homoeostasis
There is general agreement that the supraphysiological doses of oral corticosteroids which are used
in clinical medicine decrease intestinal calcium absorption and renal tubular reabsorption, leading to a negative calcium balance (1). INTESTINALCALCIUMABSORPTION The mechanisms by which net calcium transport is reduced by corticosteroids are complex and their elucidation is bedevilled by the practical problems of making physiologically relevant measurements. The result is that the data from many studies appear to conflict with each other. The effects on the intestine appear to be nonuniform, with decreased absorption in the duodenum (2), where transport is normally most active, but with generally increased absorption in the colon (3). The decline in calcium absorption seems independent of changes in circulating 1,25-dihydroxycalciferol [1,25(OH)2D ], which may increase in the early stages of corticosteroid therapy (4) (due to the development of secondary hyperparathyroidism) at the same time as absorption is declining. Intestinal and bone receptors
Supraphysiological doses of corticosteroid
,kBone formation /.f
1'Bone resorption ~ ~'Remodelling units ,4
4,Calcium abso~,on
4,Renal calcium reabsorption
\ ~,Sex hormone ,kPlasmacalcium secretion ;" ~'Parathyroid hormone secretion
Fig. 1 Pathogenesis of corticosteroid-inducedosteoporosis. 0954-6111/93/0A0015+ 07 $08.00/0
9 1993Bailli6reTindall
16 D. J. Hosking for 1,25(OH)2D are increased by corticosteroids (5), but this apparent paradox may be explained by increased catabolism of membrane-bound 1,25(OH)zD (6). Levels of the calcium-binding protein, which is 1,25(OH)2D-dependent , also decrease (7), though the way that this translates into a reduction in calcium absorption is uncertain. Although calcium uptake by membrane-bound vesicles appears unaffected by corticosteroids (8), there is enhanced N ~ K ATPase activity in the basolateral membrane of the mucosal cell (9). This may indirectly increase the back diffusion of calcium through the intercellular space between enterocytes into the intestinal lumen, due to the increased hydrostatic pressure consequent on an enhanced rate of flow of sodium and water towards the serosal surface. Dose is clearly an important consideration, and in animal experiments the decline in calcium absorption is dose dependent (10). This may reflect the result of a dose dependent increase in transcellular calcium flux, accompanied by an even larger exponential rise in calcium secretion back into the lumen so that net transport declines (11). Finally, there is the problem that the intestine adapts slowly to changes in dietary constituents (12), and many studies have not been performed under steady-state conditions. Net calcium absorption in corticosteroid-treated animals declines further with high sodium, low calcium diets (13,14), and this might be an important phenomenon in man. The problem is that the relative magnitude of these different effects is uncertain, which makes preventative measures more difficult to,identify in the clinical situation. R E N A L T U B U L A R R E A B S O R P T I O N OF C A L C I U M
Urinary calcium excretion increases at the start of corticosteroid therapy (15) and, together with the decline in intestinal calcium absorption, leads to the development of a negative calcium balance and secondary hyperparathyroidism. However, calcium excretion may not be increased in the long term (16), and it is often difficult in the clinical setting to separate changes due to an increased filtered load of calcium from those due to decreased tubular reabsorption. This is well illustrated by the reports of an increase in fasting calcium excretion during chronic corticosteroid therapy (17). While this might be due to a reduction in renal tubular reabsorption (18), it could also reflect an increased filtered calcium load from a net increase in bone resorption or the vasodilatory effect of corticosteroids increasing renal blood flow and glomerular filtration rate (19). There are also the problems of separating direct effects of corticosteroids on renal cells from those due
to secondary events, such as changes in PTH secretion, sodium excretion, or concomitant thiazide therapy. However, there are potential mechanisms by which corticosteroids could exert a direct renal effect. The kidney has classic glucocorticoid receptors (20), and renal cells contain vitamin-D-dependent calciumbinding proteins, which may be similar or identical to those in the gut (21) and may be equally impaired by corticosteroid therapy. SEX H O R M O N E P R O D U C T I O N
Sex hormones are potent regulators of the bone remodelling cycle, but their production may be reduced by corticosteroids through actions on the pituitary, gonad, or adrenal glands. In the pituitary, corticosteroids blunt the luteinizing hormone response to luteinizing hormone releasing hormone (22,23), thereby reducing gonadal production of oestrogens or testosterone. There is also clinical and experimental evidence for a direct end organ effect, as shown by the inhibition of follicle-stimulating-hormone-mediated oestrogen production by cultured granulosa cells (24) or Leydig cells (25). This effect may be mediated by a decrease in the number ofgonadotrophin-binding sites in the testes (26) or ovary. Corticosteroids also inhibit adrenocorticotrophin secretion, which in turn reduces the adrenal production of androstenedione. This may be of particular importance in postmenopausal women treated with corticosteroids, since the peripheral conversion in adipose tissue of androstenedione to oestrone is the principal source of oestrogens (27), even though it binds weakly to the oestradiol receptor on osteoblasts (28). The reduction in sex hormone production appears to have an additive effect with the increased secretion of PTH (29) and results in a shifting of the bone remodelling cycle into a persistently negative phase and makes a significant contribution to the development of osteoporosis. Understanding the mechanisms by which this occurs requires a more detailed consideration of the bone remodelling cycle.
Bone Remodelling It is fundamental to the maintenance of skeletal integrity that bone resorption and formation are coupled both temporally and quantitatively. The major effect of corticosteroids appears to be depression of osteoblastic function (Fig. 2). This can be demonstrated histomorphometrically as a reduction in mean wall thickness, lamella thickness, osteoid surface, and osteoid seam width (30). Biochemical markers of osteoblastic activity, such as osteocalcin,
Effects o f corticosteroids on bone turnover I I I
Boneloss 35%
I
4
17
Resorption > Formation Normal bone modelling unit birth rate
I
Months
I
Bone loss 43%
I _
Resorption > Formation Increased bone modelling unit birth rate
_
I__
Months
Fig. 2 Relative contributions of uncoupling of bone remodelling and birth rate of bone modelling units to production of bone loss. are also depressed (31), though they recover when, for example, bone formation increases following the successful treatment of Cushing's syndrome (32). Tissue culture experiments are in broad agreement with the clinical findings, but suggest that the effects on osteoblasts are biphasic. During the first 24 h of culture, collagen synthesis by osteoblasts is stimulated, but subsequently declines (33). The mechanism of action is believed to be through specific cytoplasmic glucocorticold receptors on osteoblasts whose activation leads to inhibition of both replication and differentiation (34,35). Osteoblasts also have a shortened life span (36), which would be consistent with changes that indicate a reduction in bone formation rate, such as the reduced mean wall thickness. Bone resorption is more difficult to assess from static histomorphometric parameters. Although resorption surfaces are increased, osteoclasts are not abundant, and this appearance could be a result of delayed infilling due to reduced bone formation rather than increased osteoclastic activity (30). Biochemical markers of bone resorption, such as hydroxyproline, increase in the early stages of corticosteroid therapy (37) but fall back to baseline values with long-term treatment (38). In this respect the findings are consistent with the temporal changes in fasting calcium excretion (15,16), The data that are available, however, are consistent in pointing to an uncoupling of
bone formation and resorption by corticosteroids leading to net bone loss. The other factor that needs consideration at this point is the role of secondary hyperparathyroidism caused by the reduction in intestinal calcium absorption and renal reabsorption. The rise in PTH seems to exacerbate the problem due to the imbalance between bone formation and resorption (39), but is not itself a primary factor. This view is supported by bone mineral density measurements in mild asymptomatic hyperparathyroidism, which show a selective reduction in cortical bone but a relative preservation of trabecular bone (40,41). It has even been suggested that hyperparathyroidism protects against age-related loss of trabecular number (42). In corticosteroid-treated patients, however, there is an additional dimension in that there is already a net loss of bone with each remodelling cycle. Since PTH increases the birth of new remodelling units, the effect of secondary hyperparathyroidism will be to amplify this uncoupling and increase the amount of bone lost per unit time (43) (Fig. 2). It may be for this reason, rather than because of any increase in bone resorption, that the combination of corticosteroid therapy and secondary hyperparathyroidism has such a deleterious effect on the skeleton. Corticosteroid-induced osteoporosis also differs from idiopathic osteoporosis in terms of the micro-
18
D. J. Hosking Corticosteroids + secondary hyperparathyroidism
Corticosteroids + control of secondary hyperparathyroidism
:
Transient gain of bone
Bone loss
I I ]
r--[
i__J F>R
Resorption>>Formation ?Bone modelling unit birth rate
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Months Corticosteroids + secondary : Corticosteroids + secondary hyperparathyroidism ', hyperparathyroidism + osteoblast stimulant _t_
84
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loss
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Formation>Resorption ?Bone modelling unit birth rate y
Months Corticosteroids + secondary hyperparathyroidism .
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i Corticosteroids + osteoblast stimulant ,, + control of secondary hyperparathyroidism i .
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l
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Months
Fig. 3 Therapeutic strategies for correction of corticosteroid-inducedosteoporosis. anatomical appearance (30). In corticosteroid-induced osteoporosis, the number of trabeculae and their surface area are relatively preserved, though individual plates are very thin (trabecular attenuation). In idiopathic osteoporosis, the major driving force to bone loss is osteoclastic resorption. Trabecular width is relatively preserved in this situation, but the lamellae are perforated by resorption, with a loss of trabecular surface and continuity. This difference has important implications for treatment, as the preservation of the thinned microanatomical structure provides the foundation on
which new bone could be deposited with restoration of mechanical integrity, only providing that bone formation could be appropriately stimulated. Plans for the treatment of established osteoporosis, however, must also take into account the role of parathyroid overactivity (Fig. 3). Although it is a contributory factor to the development of osteoporosis, it could also be harnessed to restore bone mass more quickly using stimulators of bone formation (43). If bone formation could be stimulated so that formation can exceed resorption, then the net gain of bone would be proportional to the number of osteo-
Effects o f corticosteroids on bone turnover
blasts. Since the b i r t h rate of new remodelling units is increased by P T H , this would have a favourable influence on the restoration o f b o n e mass. A l t h o u g h inhibitors o f bone resorption could lead to a n excess o f f o r m a t i o n over resorption, since the latter is already depressed by corticosteroids, the rate o f increase in b o n e would be m u c h slower t h a n with an osteoblast stimulator. It has to be emphasized, however, t h a t strategies for the prevention of corticosteroid-induced osteoporosis include measures to reduce the emergence of secondary h y p e r p a r a t h y r o i d i s m (35,44). These include m a i n tenance o f a n a d e q u a t e calcium a n d vitamin D intake, avoidance of hypercalciuria by the use of low sodium diets or thiazide diuretics, a n d the t r e a t m e n t of early evidence of hypogonadisrn. These measures need to be coupled with policies to achieve disease control with the smallest dose of a b s o r b e d corticosteroid, as well as m a i n t e n a n c e o f osteoblastic function t h r o u g h physical activity a n d the avoidance of other inhibitors, such as alcohol excess.
References
1. Nordin BEC, Marshall DH, Francis RM, Crilly RG. The effects of sex steroid and corticosteroid hormones on bone. JSteroidBiochem 1981; 15:171 174. 2. Kimberg DV, Baerg RD, Gershon E, Graudusius RT. Effect of cortisone treatment on the active transport of calcium by the small intestine. J Clin Invest 1971; 50: 1039-1044. 3. Lee DB. Unanticipated stimulatory action of glucocorticoids on epithelial calcium absorption. Effect of dexamethasone on rat distal colon. J Clin Invest 1983" 71: 322-328. 4. Hahn T J, Halstead LR, Bran DT. Effects of short term glucocorticoid administration on intestinal calcium absorption and circulating vitamin D metabolite concentration in man. J Clin Endocrinol Metab 1981; 52: 111 115. 5. K orkor AB, Kuchibotla J, Arrieh M, Gray RW, Gleason WA Jr. The effects of chronic prednisolone administration on intestinal receptors for 1,25-dihydroxyvitamin D 3in the dog. Endocrinology 1985; 117:2267 2273. 6. Carte M, Ayigbede O, Miravet L, Rasmussen H. The effect ofprednisolone upon the metabolism and action of 25-hydroxy and 1,25-dihydroxyvitamin D,. Proc Natl AcadSci USA 1974; 1: 299(~3000. 7. Feher J J, Wasserman RH. Intestinal calcium binding protein and calcium absorption in cortisol treated chicks: effects of vitamin D 3 and 1,25-dihydroxyvitamin D 3. Endocrinology 1979; 104:547-551. 8. Shultz TD, Bollman S, Kumar R. Decreased intestinal calcium absorption in vivo and abnormal brush border membrane vesicle calcium uptake in cortisol-treated chickens: evidence for dissociation of calcium absorption from brush border vesicle uptake. Proc Natl Acad Sci USA 1982; 79:3542 3546. m
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9. Charney AN, Kinsey MD, Myers L, Gianella RA, Gotts RE. Na + K* activated adenosine triphosphatase and intestinal electrolyte transport. Effect of adrenal steroids. J Clin Invest 1975; 56" 653-660. 10. Gennari C, Bernini M, Nardi P et al. Glucocorticoids: radiocalcium and radiophosphate absorption in man. In: Dixon AStJ, Russell RGG, Stamp TCB, eds. Osteoporosis, a multidisciplinary problem. London: Royal Society of Medicine, 1983: 75-80. 11. Ferretti J, Bazan JL, Alloatti D, Puche RC. The intestinal handling of calcium by the rat in vivo, as affected by cortisol. Effect of dietary calcium supplements. Calcif Tissue Res 1978; 25:1 6. 12. Malm OJ. Calcium requirements and adaptation in adult man. ScandJ Clin Lab Invest 1958; 10 (suppl. 36). 13. Adams JS, Wahl TO, Lukert BP. Effects of hydrochlorothiazide and dietary sodium restriction on calcium metabolism in corticosteroid treated patients. Metabolism 1981; 30:217 221. 14. Lukert BP, Stanbury SW, Mawer EB. Vitamin D and intestinal transport of calcium: effects of prednisolone. Endocrinology 1973; 93: 718-722. 15. Hahn TJ, Halstead LR, Strates B, Imbimbo B, Baran DT. Comparison of subacute effects of oxazacort and prednisolone on mineral metabolism in man. Calcif Tissue lnt f980; 31:10~115. 16. Hahn TJ, Halstead LR, Teitelbaum SL, Hahn BH. Altered mineral metabolism in glucocorticoid induced osteopenia. J Clin Invest 1979; 64:655 665. 17. Suzuki Y, Ichikawa Y, Saito E, Homma M. Importance of increased urinary calcium excretion in the development of secondary hyperparathyroidism of patients under glucocorticoid therapy. Metabolism 1983; 32: 151-156. 18. Reid IR, Ibbertson HK. Evidence for decreased tubular reabsorption of calcium in glucocorticoid treated asthmatics. Hormone Res 1987; 27: 200-204. 19. Field M J, Giebisch GH. Hormonal control of renal potassium excretion. Kidney lnt 1985; 27: 379-387. 20. Fuller PL, Funder JW. Mineralocorticoid and glucocorticoid receptors in human kidney. Kidney Int 1976; 10: 154-157. 21. Delorme AC, Danan JL, Mathieu H. Biochemical evidence for the presence of two vitamin D dependent calcium-binding proteins in mouse kidney. J Biochem Chem 1983; 258: 1878--1884. 22. Sakakura M, Takebe K, Nakagowa S. Inhibition of luteinizing hormone secretion induced by synthetic LRH by long term treatment with glucocorticoids in human subjects. J Clin Endoerinol Metab 1975; 40: 774-779. 23. Luton JP, Thieblot P, Valcke JC, Mahoudeau JA, Bricaire H. Reversible gonadotropin deficiency in male Cushing's disease. J Clin Endocrinol Metab 1977; 45: 488~495. 24. Hsueh AJ, Erickson GF. Glucocorticoid inhibition of ESH induced oestrogen production in cultured rat granulosa cells. Steroids 1978; 32:639 648. 25. Schaison G, Durand F, Mowszowicz I. Effect of glucocorticoids on plasma testosterone in man. Acta Endocrinol ( Copenh ) 1978; 89:126~131. 26. Saez JM, Morera AM, Haour F, Evain D. Effect of in vivo administration ofdexamethasone, corticotropin and human chorionic gonadotrophin in steroidogenesis and protein and DNA synthesis of testicular interstitial cells in prepubertal rats. Endocrinology 1977; 101: 12561263.
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27. Crilly RG, Cawood M, Marshall DH, Nordin BEC. Hormonal status in normal, osteoporotic and corticosteroid treated post menopausal women. J R Soc M e d 1978; 71: 733-736. 28. Goulding A, Gold E. Effects of chronic prednisolone treatment on bone resorption and bone composition in intact and ovariectomized rats and in ovariectomized rats receiving fl-estradiol. Endocrinology 1988; 122: 482487. 29. Eriksen EF, Coluard DS, Berg NJ et al. Evidence of estrogen receptors in normal human osteoblast like cells. Science 1988; 241: 84~86. 30. Aaron JE, Francis RM, Peacock M, Makins NB. Contrasting microanatomy of idiopathic and corticosteroid induced osteoporosis. Clin Orthop Rel Res 1989; 243: 294 305. 31. Reid IR, Chapman GE, Fraser TR et al. Low serum osteocalcin levels in glucocorticoids-treated asthmatics. J Clin EndocrinolMetab 1986; 62:379 383. 32. Pocock NA, Eisman JA, Dunstan CR, Evans RA, Thomas DH, Huq NL. Recovery from steroid induced osteoporosis. Ann Intern M e d 1987; 107:319 323. 33. Canalis EM. Effect of glucocorticoids on type I collagensynthesis, alkaline phosphatase activity, and deoxyribonucleic acid content in cultured rat calvariae. Endocrinology 1983; 112: 931439. 34. Feldman D, Dziak R, Koehler R, Stern P. Cytoplasmic glucocorticoid binding proteins in bone cells. Endocrinology 1975; 96: 29-36. 35. Lukert BP, Raisz LG. Glucocorticosteroid-induced osteoporosis: pathogenesis and management. Ann Intern M e d 1990; 112:352 364. 36. Dempster DW, Arlott MA, Meunier PJ. Mean wall thickness and formation periods of trabecular bone packets in corticosteroid-induced osteoporosis. Calcif Tissue lnt 1983; 35: 410~17. 37. Gennari C, Imbimbo B, Montagnani M, Bernini M, Nardi P, Avioli LV. Effects ofprednisolone and deflazacort on mineral metabolism and parathyroid hormone activity in humans. CalcifTissue Int 1984; 36:245 252. 38. Need AG, Hartley TF, Philcox JC, Nordin BEC. Calcium metabolism and osteoporosis in corticosteroidtreated postmenopausal women. Aust N Z J M e d 1986; 16:341 346. 39. Dempster DW. Bone histomorphometry in glucocorticoids induced osteoporosis. J Bone Miner Res ! 989; 4: 137 141. 40. Silverberg SJ, Shane E, De La Cruz L et al. Skeletal disease in primary hyperparathyroidism. J Bone Miner Res 1989; 4: 283-291. 41. Parisien M, Silverberg SJ, Shane E et al. The histomorphometry of bone in primary hyperparathyroidism: preservation of cancellous bone structure. J Clin Endocrinol Metab 1990; 70: 93(~938. 42. Bilezikien JP, Silverberg SJ, Shane E, Parisien M, Dempster DW. Characterisation and evaluation of asymptomatic primary hyperparathyroidism. J Bone Miner Res 199l; 6 (suppl 2.): 585 589. 43. Jee WSS, Clark I. Glucocorticoid induced osteoporosis. In: De Luca HF, Frost HM, Jee WSS, Johnston CC, Parfitt AM, eds. Osteoporosis. Recent advances in pathogenesis and treatment. Baltimore: University Park Press, 1981:331 342. 44. Reid IR. Pathogenesis and treatment of steroid osteoporosis. Clin Endocrino11989; 30: 83-103.
Discussion
R. Eastell Parathyroid hormone (PTH) is central to all your models of the effects of corticosteroids on bone turnover. However, the literature in this field is not all in agreement and there has been a suggestion that there is an increase in P T H sensitivity rather than an increase in the level of PTH. D. Hosking The model I have proposed is not dependent on secondary hyperparathyroidism for bone uncoupling. Secondary hyperparathyroidism increases the severity of osteoporosis. It is certainly true that a model which depends on osteoblast suppression does not depend on an increase in P T H ; increased P T H simply increases the severity of the disease. G. Boyd Is it true that fully developed osteoporosis in postmenopausal women is often associated with secondary hyperparathyroidism, and that this model can be used to investigate the potential problems of corticosteroid treatment in asthmatics? D. Hosking Possibly; the attraction of this model is that it is potentially reversible. However, corticosteroid-induced osteoporosis is, I think, different from postmenopausal osteoporosis because the microarchitecture of the bones is not the same in these two diseases. There is good evidence that in corticosteroidinduced osteoporosis, the osteoblasts are suppressed, whereas in postmenopausal osteoporosis, osteoclastic resorption increases the destruction of trabeculae. The key point is that, although not essential for the development of osteoporosis, P T H increases its severity. P T H does not have a primary effect of its own on the development of osteoporosis. N. Barnes If the problem is suppression of osteoblasts and you discontinue oral corticosteroid therapy before major damage is effected, how long does it take for the osteoblasts to begin behaving normally? Can the osteoblasts undo the damage and remodel the bone that has been lost? D. Hosking l think there is evidence of recovery from corticosteroid-induced osteoporosis. If Cushing's syndrome is treated, there is an increase in osteocalcin within a few weeks and bone mineral density increases. That is why the preservation of the microarchitecture is so important. If the microarchitecture is in place, it is possible to restore bone function as well as mass. If the microarchitecture is lost, making the small pieces of bone bigger does not increase the mechanical integrity.
Effects o f corticosteroids on bone turnover N. Barnes But is there evidence that you do get increases in bone mass when corticosteroid treatment is discontinued? Does the bone density return to normal? D. Hosking No, the bone mass does not return completely to normal, though some recovery does occur.
21
N. Barnes Is there evidence that fluoride would be particularly useful in corticosteroid-induced osteoporosis? D. Reid I think many people would say that there is, because the histomorphology data show restoration to normal levels.