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
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Introduction
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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 Cushings 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 Cushings
syndrome and in control subjects. As they point out, their study has a
number of significant strengths. By studying patients with Cushings
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 Cushings
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.
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Mechanisms of glucocorticoid effects on bone
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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
Cushings 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 Cushings 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 Cushings
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.
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Distribution of steroid-induced bone loss
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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 Cushings 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.
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Conclusions
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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 Cushings syndrome should be
substantially reduced.
Received March 31, 1998.
Accepted April 2, 1998.
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