The Role of Parathyroid Hormone in the Pathogenesis of Glucocorticoid-Induced Osteoporosis: A Re-Examination of the Evidence

Mishaela R. Rubin and John P. Bilezikian

Departments of Medicine (M.R.R., J.P.B.) and Pharmacology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032

One of the most important of the secondary causes of osteoporosis is chronic exposure to glucocorticoids, which are used for an extraordinarily large number of disorders. The adverse effects of hypercortisolism on bone metabolism were recognized more than half a century ago (1). Today, glucocorticoid exposure in the context of medicinal use has become far more common than excess endogenous exposure (Cushing’s syndrome). Glucocorticoid-induced osteoporosis (GIO) is the third most common cause of osteoporosis, trailing only postmenopausal and age-related osteoporosis (2). As many as 50% of individuals on chronic glucocorticoid therapy will suffer an osteoporotic fracture (3). Recently, a large-scale retrospective cohort study by Van Staa et al. (4) in England clearly demonstrated that fracture risk is increased across virtually the entire dosage range of oral glucocorticoids. A large number of subjects with a history of glucocorticoid exposure (n = 244,235) were matched to the same number of control patients who had no history of glucocorticoid exposure. The average age of the subjects was 57 yr; respiratory diseases were the common indication for therapy, being prescribed in 40% of the patients (4). Referent to nonglucocorticoid users, subjects with a history of glucocorticoid therapy had significantly greater risk for fractures at the spine (rr = 2.6), the hip (rr = 1.6), and at any nonvertebral site (rr = 1.3). The magnitude of the fracture risk was directly related to dosage, with subjects receiving as little as 2.5 mg of prednisolone at significantly greater risk than control subjects (4). Bone loss from glucocorticoid use was also found to occur rapidly, within the first 3 months of treatment. A similarly precipitous loss of bone mass has also been observed prospectively when glucocorticoids are used in the setting of organ transplantation (5, 6), and in other clinical situations (7, 8, 9, 10). Even inhaled steroids have been implicated as a cause of bone loss (11, 12).

The cardinal feature of GIO on skeletal dynamics is a reduction in bone formation. Bone formation is inhibited, in part, through a decrease in osteoblast life span and function. Histomorphometric studies demonstrate a marked reduction in indices of bone formation, such as reduced mineral apposition rate and prolonged mineralization lag time. The amount of bone that is replaced in each remodeling cycle can be reduced by as much as 30% (13, 14, 15, 16, 17). Biochemical markers of bone formation, osteocalcin and bone-specific alkaline phosphatase, are suppressed. In addition to this primary suppressive effect on bone formation, glucocorticoids also induce an early phase of accelerated bone resorption (18). Osteoclast number and activity increase, along with an increase in the fraction of eroded bone surface (14, 15). Biochemical markers of bone resorption, urinary N-telopeptide and pyridinoline cross-link excretion, rise during early glucocorticoid exposure (17, 19, 20). This early phase of glucocorticoid use, therefore, can be associated with rapid bone loss due to both reduced bone formation and accelerated bone resorption. With continued use of glucocorticoids, the rapid rate of osteoclast-mediated bone resorption slows (14), but suppression of bone formation continues as the dominant skeletal dynamic. Thus, bone loss is progressive because bone resorption chronically exceeds bone formation. Although bone loss due to glucocorticoid use tends to be diffuse, the axial skeleton is targeted preferentially. The cancellous bones of the vertebral spine are typically affected, whereas cortical bone sites of the appendicular skeleton (i.e. forearm) are affected to a lesser extent (21, 22). Spontaneous fractures of the vertebrae or ribs are common complications of GIO (23).

Etiology of GIO

The pathogenesis of GIO is multifactorial (Fig. 1Go; Ref 24). Reduction of gonadal hormones is an important mechanism through the inhibitory effects of glucocorticoids on the pituitary gonadotropins (19). Glucocorticoids blunt the secretion of LH in response to GnRH in men and women (25, 26), inhibit the action of FSH, and reduce gonadal sex steroid production (27, 28, 29, 30, 31). In one study, asthmatic men treated with prednisone at an average daily dose of 12 mg had significantly lower free and total testosterone levels and higher LH and FSH levels than age-matched control subjects (29). Similarly, estrogen levels decline with glucocorticoid administration (30, 31).



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Figure 1. The classical pathophysiology of GIO. The shaded area is the focus of attention in this paper.

 
However, the adverse effects of glucocorticoids on bone are not mediated exclusively by sex-steroid deficiency (29, 32, 33). Other proposed mechanisms for GIO include the effects of glucocorticoids on the expression of locally produced growth factors and related proteins (18). Prolonged exposure to high levels of glucocorticoids results in reduced production of IGF-I, a trophic factor for bone, as well as alterations in IGF-binding proteins in osteoblasts (34, 35). Hepatocyte growth factor, a polypeptide with a mitogenic effect on osteoblasts (36, 37), is also decreased with glucocorticoid administration (38, 39). Loss of muscle strength and reduced physical activity also probably contribute to the bone loss that occurs with glucocorticoids (40).

Dynamic studies

Another proposed mechanism for the adverse skeletal effects of glucocorticoids is a direct effect on calcium metabolism. At daily doses of prednisone, 10 mg, intestinal calcium absorption is reduced (41, 42). Alterations in vitamin D metabolism or an independent noncompetitive effect to counter the actions of vitamin D (43) could account, in part, for reduced intestinal calcium absorption. When prednisone doses are increased to 20 mg/d or higher, a direct effect to increase renal calcium excretion adds to negative calcium balance (44, 45). Physiologically, if the serum calcium is reduced as a result of reduced calcium absorption and increased urinary calcium excretion, one would expect to find evidence for a secondary increase in PTH secretion. The state of secondary hyperparathyroidism would then be expected to lead to patterns of bone loss typified by excessive PTH secretion, namely cortical bone loss.

Hahn et al. (46) compared 17 glucocorticoid-treated patients with normal subjects and found increases in PTH, along with decreases in 47Ca absorption and forearm bone mass. Similar findings were noted in other small studies when patients on glucocorticoid therapy were found to have increases in PTH (47, 48). In a larger study by Suzuki et al. (45), 44 glucocorticoid-treated patients were also found to have elevated PTH, nephrogenous cAMP, and fasting urinary calcium. Recently, elevated PTH levels were observed in infant piglets administered dexamethasone for 15 d (49).

Thus, a classic model of GIO on bone invariably includes a compensatory increase in PTH due to these proposed effects of glucocorticoids on gastrointestinal and urinary calcium metabolism (19). Some studies have suggested that concomitant vitamin D deficiency or resistance could contribute to the reductions in calcium absorption or conceivably also lead more directly to PTH secretion (50). In some trials, when calcium or vitamin D was replaced, the rise in PTH levels was attenuated (46, 48, 51), but this has not been consistently found in other studies (52, 53).

A possible mechanism by which glucocorticoids increase PTH levels is through a direct effect on the glandular secretion of PTH (54). This might occur via increased PTH gene transcription (55) and enhanced efficiency of postreceptor signaling (56, 57). Another mechanism by which glucocorticoids might affect the parathyroid-bone axis is by increasing the sensitivity of bone cells to PTH. Glucocorticoids have been shown to increase the expression (58) and availability (56) of PTH receptors on osteoblasts. Increased numbers of PTH receptors could be associated with enhanced sensitivity to PTH. Alternatively, enhanced sensitivity to PTH could be due to changes in the affinity of the receptor for PTH. In mouse cell cultures, the addition of a defined concentration of glucocorticoids has a synergistic effect on PTH-mediated bone resorption (59, 60).

These models and the supporting evidence for them might be expected to have specific consequences. For example, PTH levels might be consistently elevated when glucocorticoids are used. Second, measurements of bone mass might reflect the known skeletal effects of excessive PTH on bone to erode cortical bone and to help maintain cancellous bone. Third, histomorphometric analysis of bone biopsies from individuals on glucocorticoid therapy might be expected to show evidence for the actions of PTH on bone to increase indices of bone remodeling. Evidence available in support of or against these expectations is reviewed here.

Circulating PTH concentration in the presence of glucocorticoids

As early as 1980, Seeman et al. (61) observed that excess glucocorticoid levels, whether endogenous or exogenous in origin, were not associated with alterations in PTH levels. Similarly, Slovik et al. (53) found normal PTH levels in asthmatic patients on short-term and long-term glucocorticoid treatment. In addition, 22 women with rheumatoid arthritis were found to have the same PTH levels whether or not they were receiving low dose prednisone (6.6 mg/d; Ref. 62). When women were administered even higher amounts of prednisone chronically (for an average of 13 yr), PTH levels were the same as in age-matched controls (63). Hattersley et al. (64) also found no difference in PTH levels in patients treated with chronic glucocorticoids for obstructive airway disease when compared with controls. The expectation that PTH levels should have been elevated in these studies, given increases in urinary calcium excretion and decreases in intestinal calcium absorption is not confirmed by the data. It is important to note, however, that the subjects in these trials had underlying medical illnesses, which could conceivably have modified both the secretion of and skeletal response to PTH.

Other data indicating that PTH levels are not changed by glucocorticoid administration come from studies in normal, healthy subjects. In three separate investigations examining the effects of a short course (5–14 d) of prednisone (doses ranging from 15–40 mg daily) in healthy adults, no significant change in PTH levels was found (52, 64, 65). In a longer study of 9 healthy men who were administered 50 mg prednisolone daily for as long as 6 months, there was no change in PTH levels (Fig. 2Go; Ref. 66). These studies in normal subjects confirm those in specific medical illnesses and help to minimize any potential confounding effects of underlying illness on circulating PTH levels. However, as already noted, it remains possible that skeletal responsiveness to PTH is differentially affected by glucocorticoids without any change in PTH concentrations. Thus, even a normal PTH level might elicit significant physiological effects, such as an elevation in the level of cAMP (45, 48).



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Figure 2. Glucocorticoids do not increase PTH levels. Nine healthy men receiving 50 mg of prednisolone daily for infertility (due to the presence of antisperm antibodies) for 3.7 ± 0.6 months. PTH did not increase during corticosteroid treatment. The area above the dotted line represents the normal area for PTH. [Reprinted with permission from G. Pearce et al.: J Clin Endocrinol Metab 83:801–806, 1998 (66 ) ©The Endocrine Society.]

 
Most recently, Manelli et al. (67) have studied PTH secretory dynamics in glucocorticoid-treated men, as compared with normal age- and sex-matched controls. Six men (ages, 31–64 yr) treated chronically with glucocorticoids (daily dose > 7.5 mg of prednisone or equivalent for more than 6 months) and control subjects underwent peripheral blood sampling every 3 min for 6 h. Basal PTH secretory rate was reduced in the glucocorticoid-treated group (4.3 vs. 8.8 pg/ml·min; P = 0.017) despite an increase in amplitude of fractional pulsatile PTH secretion (42 vs. 18 pg/ml·min; P = 0.006) as compared with controls. Chronic glucocorticoid treatment appeared to induce a redistribution of the spontaneous PTH secretory profile by reducing the amount tonically released while increasing the amount released by pulsatile secretion (67). Although the overall dominant effect was a reduction in PTH secretion, this study could not determine whether tonic or pulsatile secretion was the driving force. If such a distinction could have been made, the principal action of glucocorticoids on PTH, positive or negative, could have been elucidated. Thus, although the implication of the studies in which PTH levels are measured favor an inhibition by glucocorticoids, more direct evidence requires an examination of the skeleton per se.

Densitometric studies

Densitometric findings further support the idea that PTH is not involved in the pathophysiological mechanisms of bone loss in GIO. The typical pattern of bone loss in GIO is a preferential reduction of lumbar spine and trochanteric bone mineral density (BMD), significantly greater than any reduction at the distal radius (Fig. 3AGo) (22, 68, 69, 70, 71). Reid et al. (69), however, reported that the mean decrement in BMD in their steroid-treated patients was approximately 20% in the distal forearm, lumbar spine, and proximal femur as assessed by single-photon absorptiometry or dual-energy x-ray absorptiometry (DXA). The application of quantitative computed tomography (QCT) helped to distinguish cancellous elements in the lumbar spine from its cortical elements. Reid et al. (69) showed, using QCT, that the mean decrement in lumbar spine BMD was much greater, approximately 40%. These observations lend further support to the idea that glucocorticoids reduce cancellous bone density preferentially. Some of this cancellous reduction, however, could be due to expanded marrow space.



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Figure 3. A, Bone mineral content in prednisone-treated patients with rheumatoid arthritis, as compared with age- and sex-matched patients with rheumatoid arthritis never treated with glucocorticoids. [Adapted from R. F. Laan et al.: Calcif Tissue Int 52:5–9, 1993 (68 ).] B, Bone densitometry in primary hyperparathyroidism. Data are shown in comparison with age- and sex-matched normal subjects. Divergence from expected values is different at each site (P = 0.0001). [Adapted from S. J. Silverberg et al.: J Bone Miner Res 4:283–291, 1989 (73 ).]

 
Primary hyperparathyroidism is an ideal model for PTH-induced bone loss. The preferential action of PTH to be catabolic at cortical sites (e.g. distal one third radius site) is typically seen in primary hyperparathyroidism (72, 73). In contrast, the lumbar spine, a site of predominantly cancellous bone, is relatively well preserved (Fig. 3BGo; Ref. 74). Even in postmenopausal estrogen-deficient women with primary hyperparathyroidism, cancellous bone of the lumbar spine is relatively well protected. This pattern is seen in those with mild primary hyperparathyroidism. With more severe disease and prolonged PTH exposure, however, this pattern can be altered, and skeletal loss at all sites can occur.

Measurements of BMD in primary hyperparathyroidism differ from those observed in GIO (Table 1Go). Admittedly, the densitometric patterns of primary hyperparathyroidism and GIO cannot be directly compared because each results from different mechanisms of skeletal loss. In primary hyperparathyroidism, bone turnover is increased at both formation and resorption sites, whereas in GIO, bone resorption is uncoupled from bone formation which is suppressed. One can account for preferential loss of cancellous bone in GIO due to the intrinsic, higher turnover rate of cancellous bone compared with cortical bone. If PTH is influencing bone dynamics in GIO, suppressed bone formation would not be expected because PTH increases bone formation rates. It is noteworthy that preservation of cancellous bone in mild primary hyperparathyroidism is in contrast to the pattern of bone loss in GIO in which cancellous bone loss is commonly seen. If compensatory hyperparathyroidism is playing an important role in GIO, one might expect to see evidence that it counteracts the actions of glucocorticoids on cancellous bone density, much in the way that PTH counteracts the effects of estrogen deficiency on cancellous bone loss. Moreover, although there is some evidence of cortical bone loss with GIO (4, 69), as there is evidence for some cancellous bone loss in primary hyperparathyroidism, it is the distinctly different patterns that are most striking.


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Table 1. Comparison of the densitometric and fracture risk profiles of GIO and primary hyperparathyroidism

 
Bone density predicts fracture risk. In states of glucocorticoid excess, the vertebral compression fracture is common, reflecting the major reduction in BMD at this site. In states of PTH excess, vertebral fractures are most uncommon. Although epidemiological data on site-specific fracture incidence is incomplete, it would appear that the forearm fracture is much more likely to occur in primary hyperparathyroidism than the vertebral fracture (75, 76). However, it is important to realize that fracture risk is due to many factors, in addition to bone density, PTH, and glucocorticoids. The attribution of an endpoint, fracture to specific risks such as PTH or glucocorticoids might be too simplistic and somewhat misleading.

Histomorphometric studies

Nevertheless, direct histomorphometric analysis of bone biopsies also suggests a relatively minor role for PTH in the bone loss associated with glucocorticoid use. In GIO, there is a decrease in wall thickness of trabecular packets, in trabecular thickness, and in cancellous bone volume (Fig. 4Go; Refs. 15 and 77). In primary hyperparathyroidism, the predominant picture is different, namely cortical thinning (78) with maintenance of cancellous bone volume (Fig. 5Go).



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Figure 4. Differing effects of glucocorticoids on bone. Photomicrograph of murine vertebral cancellous bone in a mouse receiving placebo (A) and a mouse receiving prednisone (B). Note the marked reduction in vertebral cancellous bone area in the mouse vertebrae receiving prednisone. [Reprinted with permission from R. S. Weinstein et al.: J Clin Invest 102:274–282 (84 ).]

 


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Figure 5. Scanning electron micrographs of iliac crest biopsies of a patient with primary hyperparathyroidism (top) and an age- and sex-matched control subject (bottom). Note the thinning of cortices in the patient with primary hyperparathyroidism as well as the maintenance of cancellous bone and trabecular connectivity. [Reprinted with permission from M. Parisien et al.: J Clin Endocrinol Metab 70:930–938, 1990 (78 ) © The Endocrine Society.]

 
Furthermore, trabecular connectivity is relatively well maintained in primary hyperparathyroidism (79), whereas in GIO trabecular microarchitecture is typically disrupted with a reduction in connectivity (15, 77, 80). In primary hyperparathyroidism, the expected age-dependent decline in trabecular number and the increase in trabecular separation do not occur. Trabecular plates and their connections are maintained over time more effectively than would be expected through the aging process (79, 81). Primary hyperparathyroidism seems to retard the normal age-related processes associated with trabecular loss. In GIO, trabecular number is reduced and trabecular separation is increased, findings quite different from the analysis in primary hyperparathyroidism.

Dynamic histomorphometric indices provide further contrasts between PTH and GIO-associated bone loss. The early phase of glucocorticoid use is associated with increased osteoclast activity and, in this respect, is similar to the accelerated bone resorption of primary hyperparathyroidism. Chronic glucocorticoid use decreases the bone formation rate and shortens the life span of the active osteoblastic population (15). The mineralization rate and adjusted apposition rate fall, consistent with a decrease in bone turnover (13). Osteoid seam thickness is normal or reduced (14, 15). PTH, in contrast, increases bone formation by enhancing the number and activity of osteoblasts (81, 82). Mineralization rate and adjusted apposition rate rise, along with a widening of the osteoid seams (81). A summary of these comparisons is presented in Table 2Go. However, it is important to realize that the histomorphometric effects of PTH and glucocorticoids when considered together could be different from their individual effects.


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Table 2. Comparison of histomorphometric parameters in GIO and primary hyperparathyroidism

 
Cellular processes associated with glucocorticoid-induced bone loss

Glucocorticoids and PTH have differing effects on the life span of bone cells. Along with an elevation in bone formation rate, glucocorticoids reduce osteoblast number (83). They both suppress osteoblastogenesis and promote apoptosis of mature osteoblasts and osteocytes (84). A mouse model of glucocorticoid bone loss revealed increased osteoblast apoptosis in the vertebrae and increased apoptosis of osteocytes in the metaphyseal cortical bone (84). These changes were confirmed in patients receiving long-term glucocorticoid therapy when the head of the femur was removed at surgery and the bone tissue was evaluated directly (83, 84). PTH, in contrast, has an antiapoptotic effect on osteoblasts. Daily PTH injections in mice with either normal bone mass or osteopenia due to defective osteoblastogenesis increased their bone formation rate without affecting the generation of new osteoblasts. Instead, PTH increased the life span of mature osteoblasts by preventing apoptosis (85).

PTH and glucocorticoids also have different effects at the cellular level, when the receptor activator of nuclear factor-{kappa}B ligand (RANKL)-osteoprotegerin system is considered. An increase in the cytokine RANKL, expressed in committed preosteoblastic cells (86), leads to enhanced osteoclast activity and bone resorption (87, 88). Glucocorticoids down-regulate the production of osteoprotegerin, a decoy receptor that binds RANKL and thereby inhibits its activities at the functional receptor, RANK (89, 90). The interaction between RANKL and RANK on the committed osteoclast cell line is thus facilitated. This mechanism could account for the early phase of osteoclastic bone resorption with glucocorticoids. Recently, administration of osteoprotegerin was shown to prevent bone loss in a rat model of glucocorticoid-induced osteopenia (91). When PTH is administered continuously, the effects on RANKL and osteoprotegerin are similar to those observed with glucocorticoids, with an increase in RANKL and a decrease in osteoprotegerin (92, 93). However, when PTH is administered in an intermittent fashion, the effects differ from those observed with glucocorticoids and continuous PTH. The alterations in RANKL and osteoprotegerin are only transient (92) or do not occur at all (94), perhaps favoring an osteoblast effect in bone. Most recently, new evidence has emerged that a fusion protein derivative of RANKL can stimulate anabolic bone formation in mice (95). The effects of glucocorticoids and PTH on the RANKL-osteoprotegerin system require more careful examination.

PTH as anabolic therapy in osteoporosis

The final area to discuss focuses on the anabolic effect of PTH on cancellous bone in clinical trials of osteoporosis. This anabolic effect, observed both in postmenopausal osteoporosis and men with osteoporosis, and key for this discussion, in GIO, raises further questions about an important effect of PTH in mechanisms of GIO-induced bone loss.

The potential of PTH as an anabolic agent for osteoporosis treatment was first noted over 70 yr ago (96). Numerous trials since have shown that intermittent, low-dose PTH administration results in impressive increases in spine BMD. The potential for anabolic skeletal actions of PTH is seen in the common disorder of PTH excess, primary hyperparathyroidism. As noted above, in the mild, asymptomatic form of primary hyperparathyroidism, the cancellous skeleton of the lumbar spine is relatively well preserved, whereas the cortical skeleton is preferentially reduced (97). The enhanced cancellous bone volume and trabecular plate connectivity have supported the idea that PTH could be a useful anabolic therapy for osteoporosis.

Over the past 5 yr, numerous clinical trials of PTH administration, ranging from 1–3 yr in duration, have been performed in over 2500 patients. The principal finding common to all studies in both men and women is a marked increase in spine BMD with PTH (98, 99, 100, 101). This increase in BMD is substantially greater than the increase commonly observed after 1 yr of antiresorptive therapy. By DXA, increases of 7–10% annually and by QCT increases of 40% or more are seen. The difference between these two densitometric techniques reflects the rather exclusive measurement of cancellous bone by QCT in contrast to DXA, which detects both cortical and cancellous elements in the lumbar spine. Bone density at the hip site increases, but not as impressively. Forearm density either remains the same or declines slightly with treatment. Total body bone mineral increases. The largest trial to date, by Neer et al. (102), tested daily administration of PTH in 1637 women with postmenopausal osteoporosis. In addition to impressive increases in BMD (spine, 10–14%; total hip, 3–4%; total body bone mineral, 3–5%), there was a significant 65–69% risk reduction of vertebral fractures and 35–40% risk reduction of nonvertebral fractures.

PTH treatment for GIO

PTH was shown by Lane et al. (16) to be efficacious in GIO. In a 12-month, controlled trial, 51 postmenopausal women on hormone replacement therapy and steroids were randomly assigned to receive human PTH (1–34) or no PTH for 1 yr (placebo injections were not used). In the PTH treatment group, vertebral bone density increased 35% by QCT and 11% by DXA (Fig. 6Go). Total hip bone density increased by 2% in the PTH group by DXA, whereas forearm density did not significantly change (16). Serum indices of bone formation rose in the first 3 months, whereas resorption markers peaked later at 6 months (16), consistent with a dynamic that favors bone formation. Twelve months after PTH withdrawal but continued estrogen use, bone density increased further (103). Cumulative changes over 2 yr in the PTH group were 45.9% by QCT in the vertebral spine and 12.6%, 4.7%, and 5.2% in the vertebral, total hip, and femoral neck by DXA, respectively. The estrogen-only group, in comparison, did not demonstrate any significant changes in spine or hip bone density. Both groups had a slight decrease of forearm bone density (1.5%) over the 2-yr period. Bone markers returned to baseline within 6 months after stopping PTH.



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Figure 6. Changes in lumbar spine BMD in postmenopausal women on hormone replacement therapy and steroids given human PTH (1–34) or estrogen for 12 months, as measured by QCT (A) and DXA (B). Between 12 and 24 months, both groups received estrogen only. *, P < 0.001 between groups at 12 months and 24 months. [Reprinted with permission from N.E. Lane et al.: J Bone Miner Res 15:944–951, 2000 (103 ).]

 
These data establish that intermittent administration of PTH, in combination with estrogen, is effective in increasing bone density among postmenopausal women being treated with glucocorticoids. It is not known, however, whether continuous, low-dose administration of PTH would lead to the same favorable response as seen when intermittent PTH is used according to the paradigm of Lane et al. (16). This information would help to sort out the possibility that PTH could contribute to and yet be beneficial in GIO.

Conclusion

The evidence reviewed in this paper indicates that among the many putative mechanisms for GIO, secondary increases in PTH would appear no longer to have unambiguous, compelling support. Although not without question, the balance of evidence from epidemiology, bone densitometry, histomorphometry, bone biology, and PTH therapeutics points away from the conventional wisdom that disrupted regulation of PTH is involved in GIO. In an irony that can only be interpreted as the slow and inexorable quest for truth, we now are touting the potential benefits of PTH in GIO rather than its liabilities.

Acknowledgments

We acknowledge helpful discussions with Drs. Elizabeth Shane and Shonni Silverberg (Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY).

Footnotes

Address all correspondence and requests for reprints to: John P. Bilezikian, M.D., Department of Medicine, College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. E-mail: jpb2@columbia.edu.

This work was supported by National Institutes of Health Grant DK- 32333.

Abbreviations: BMD, Bone mineral density; DXA, dual-energy x-ray absorptiometry; GIO, glucocorticoid-induced osteoporosis; QCT, quantitative computed tomography; RANKL, receptor activator of nuclear factor-{kappa}B ligand.

Received January 4, 2002.

Accepted May 30, 2002.

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