Glucocorticoid Effects on Bone

Ian R. Reid

University of Auckland Auckland, New Zealand

Address correspondence and requests for reprints to: Ian R. Reid, Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: i.reid{at}auckland.ac.nz


    Introduction
 Top
 Introduction
 Mechanisms of glucocorticoid...
 Distribution of steroid-induced...
 Conclusions
 References
 
IT IS now nearly 70 years since Harvey Cushing described the syndrome of glucocorticoid over-production that now bears his name (1). In his original series, the development of osteoporosis with spontaneous fractures was noted as being a significant contributor to the morbidity associated with this condition, and it remains so today. While Cushing’s syndrome is relatively uncommon, the therapeutic use of glucocorticoid drugs is widespread and often lifesaving. Thus, the actions of glucocorticoids on bone are not merely an esoteric concern of endocrinologists, but are relevant to virtually all practicing physicians.

Despite the passage of so many years since the description of steroid osteoporosis, significant uncertainties remain regarding its mechanisms and its ultimate effects on bone density. A number of these issues are brought nicely into focus by the paper of Chiodini et al. (1a) in this issue of JCEM (see page 1863). These workers have compared biochemical indices of calcium metabolism and provided measurements of bone density in eumenorrheic women with Cushing’s syndrome and in control subjects. As they point out, their study has a number of significant strengths. By studying patients with Cushing’s syndrome and normal gonadal function (both by clinical and biochemical criteria) they have eliminated any possible contributions to their findings from other underlying diseases and hypogonadism. This is valuable in providing an assessment of the effects of glucocorticoids on bone, though it should be remembered that this situation deviates from the common clinical scenario in which glucocorticoid osteoporosis occurs, in which systemic diseases such as rheumatoid arthritis are usually present, and in which hypogonadism, particularly in men (2), is the norm. Despite the careful design of this study, it is still not completely free of some potentially complicating factors. In particular, the authors point out the bimodal distribution of adrenal androgen levels in their subjects, as some had pituitary Cushing’s syndrome and others had adrenal adenomas. However, this study produces clear evidence of increased bone resorption, reduced osteoblast activity, hyperparathyroidism, hypercalciuria, and marked loss of trabecular bone. These findings with respect to the mechanisms of steroid osteoporosis and its ultimate effects on bone mass, are generally consistent with previous published evidence, although some areas of controversy remain. These will now be discussed.


    Mechanisms of glucocorticoid effects on bone
 Top
 Introduction
 Mechanisms of glucocorticoid...
 Distribution of steroid-induced...
 Conclusions
 References
 
There is consistent evidence from a substantial number of studies that long-term exposure of the osteoblast to glucocorticoids results in decreased cell proliferation and reduced protein synthesis. Reduction in osteoblast proliferation is associated with reduced expression of cyclin-dependent kinases and cyclin-D3, together with enhanced transcription of inhibitors of cyclin-dependent kinases (3). The reduction in protein synthesis by osteoblasts is probably mediated by direct glucocorticoid receptor regulation of a number of important osteoblast genes, including those for type I collagen, osteocalcin, osteopontin, fibronectin, ß-1 integrin, bone sialoprotein, alkaline phosphatase, collagenase, and the nuclear proto-oncogenes c-myc, c-fos, and c-jun. These in vitro findings are consistent with histomorphometric studies in both animals and man (4), showing reduced osteoblast numbers and bone formation, and with clinical assessments of circulating osteoblast markers, particularly osteocalcin (5). In this respect, the study of Chiodini is quite consistent with previously published data.

There is a lack of unanimity, however, with respect to the effects of glucocorticoids on bone resorption. This may be because any such effects are less marked than those on osteoblasts, but it is also likely to have its origin in the opposing effects of glucocorticoids at different stages in the osteoclast life cycle, promoting osteoclast formation from precursor cells in bone marrow (6, 7), but increasing apoptosis in mature osteoclasts (8, 9). The balance of these opposing effects may vary from one clinical context to another, with apparently contradictory results in clinical studies. As Chiodini et al. point out, previous cross-sectional studies in subjects with Cushing’s syndrome have usually demonstrated normal values for biochemical indices of bone resorption. This has also been the finding in a number of recent prospective studies of glucocorticoids in either normal subjects or in patients with a variety of different underlying conditions. These studies do not provide support for the concept that increased bone resorption is a major contributor to steroid-induced bone loss. Studies of bone histomorphometry are similarly equivocal. The extent of eroded surfaces appears to be increased (10, 11); however, much of this surface does not contain active osteoclasts, and some studies have actually shown osteoclast numbers to be decreased (12). This has been interpreted as reflecting an inhibition of recruitment of osteoblasts to the eroded surface (leaving eroded surfaces unfilled for a greater time than is normal) rather than as an acceleration of bone resorption itself. Similarly, studies of bone tissue in vitro demonstrate either increased (13) or unchanged (14) bone resorption, depending on the conditions under which the cultures are carried out.

It is also possible that the discrepancy, with respect to markers of resorption, between the present study and those previously published has quite another origin. The excretion of both hydroxyproline and deoxypyridinoline has been expressed as a ratio to creatinine. Urine creatinine excretion is primarily a function of muscle mass, and muscle mass is substantially reduced in Cushing’s syndrome as part of the generalized wasting of connective tissue that occurs. For example, decreases in lean body mass of 20% have been documented in Cushing’s syndrome (15). Thus, much of the apparent increase in urinary bone resorption markers could be accounted for in this way. The measurement of serum bone resorption markers will be important in addressing this issue.

As Chiodini et al. point out, there is greater agreement with their finding that circulating concentrations of parathyroid hormone are increased in patients with glucocorticoid excess, though this is by no means a universal finding (16). Hyperparathyroidism has been demonstrated with acute infusions of glucocorticoids (17) and in prospective studies extending over periods of weeks (18). In vitro studies of parathyroid tissue from rats (19), cattle (20), and humans (17) indicate that glucocorticoids can directly stimulate hormone secretion. In vivo, it is possible that calcium malabsorption in both the gut and the renal tubule increase circulating concentrations of this hormone. However, the point is well made by Chiodini et al. that hyperparathyroidism is likely to be a relatively minor contributor to the development of steroid osteoporosis.


    Distribution of steroid-induced bone loss
 Top
 Introduction
 Mechanisms of glucocorticoid...
 Distribution of steroid-induced...
 Conclusions
 References
 
The findings of the Chiodini study with respect to bone loss are broadly consistent with previous data (21). Integral bone mineral density of the lumbar spine and femur is reduced about 20%, whereas axial trabecular bone shows a deficit of approximately twice this size. In the peripheral skeleton, a similar difference between trabecular and cortical loss is demonstrated, although overall the loss of bone appears to be less marked peripherally than axially. It is not clear, however, that these differences are statistically significant. The more rapid loss of trabecular bone is probably a reflection of its greater surface-to-volume ratio. Since bone remodeling takes place only at bone surfaces, trabecular bone responds more rapidly to either positive or negative changes in bone balance. As a result, the vertebral bodies and ribs are the typical sites of fracture both in Cushing’s syndrome and in patients using glucocorticoid drugs long-term.

These considerations have practical relevance in the clinic. When assessing the bone density of a steroid-treated patient, it is important that a trabecular-rich site is measured. The spine is most commonly used, and while anteroposterior dual-energy x-ray absorptiometry scans are quite satisfactory, quantitative computed tomography or dual-energy x-ray absorptiometry in the lateral projection probably are more sensitive indicators of this particular form of osteoporosis. As demonstrated in the present study, an assessment of peripheral, cortical bone may grossly underestimate the amount of bone loss that has taken place and may therefore lead to inappropriate therapy decisions. The Chiodini study contains the novel observation that bone density is inversely related to urine free cortisol excretion. This parallels the observation made in steroid-treated patients that the severity of bone loss is related to the dose and duration of glucocorticoid therapy. Thus, these immediately available pieces of clinical information are important in the initial evaluation of a steroid-treated subject.


    Conclusions
 Top
 Introduction
 Mechanisms of glucocorticoid...
 Distribution of steroid-induced...
 Conclusions
 References
 
While there is certainly scope for further research into both the etiology and assessment of steroid osteoporosis, it is quite clear that its etiology is multifactorial but that the osteoblast is probably the principal site of glucocorticoid action on bone. Similarly, there is abundant evidence for a widespread loss of bone throughout the skeleton, which is more marked in trabecular bone, leading to fractures in trabecular sites such as the spine. Perhaps most importantly, there are now effective methods for preventing and treating steroid osteoporosis (22). The value of bisphosphonates in this role has been known for more than a decade (23), and the anti-fracture efficacy of both etidronate (24) and alendronate has now been demonstrated. Sex hormone replacement in either men (25) or women (26) with hypogonadism is of benefit. There is also some evidence supporting the use of calcitonin (27), calcitriol (28), and calcium supplements (29). The availability of safe and effective methods for preventing steroid osteoporosis make it mandatory that an assessment of future fracture risk be carried out in any patient exposed to glucocorticoids long-term and that interventions to preserve the skeleton be provided where indicated. In this way, the incidence of fractures in both steroid-treated patients and those with Cushing’s syndrome should be substantially reduced.

Received March 31, 1998.

Accepted April 2, 1998.


    References
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 Introduction
 Mechanisms of glucocorticoid...
 Distribution of steroid-induced...
 Conclusions
 References
 

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