Abstract
Glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis. Fractures, which are often asymptomatic, may occur in as many as 30–50% of patients receiving chronic glucocorticoid therapy. Vertebral fractures occur early after exposure to glucocorticoids, at a time when bone mineral density (BMD) declines rapidly. Fractures tend to occur at higher BMD levels than in women with postmenopausal osteoporosis. In human subjects, the early rapid decline in BMD is followed by a slower progressive decline in BMD. Glucocorticoids have direct and indirect effects on the skeleton. The primary effects are on osteoblasts and osteocytes. Glucocorticoids impair the replication, differentiation and function of osteoblasts and induce the apoptosis of mature osteoblasts and osteocytes. These effects lead to a suppression of bone formation, a central feature in the pathogenesis of GIO. Glucocorticoids also favor osteoclastogenesis and as a consequence increase bone resorption. Bisphosphonates are effective in the prevention and treatment of GIO. Anabolic therapeutic strategies are under investigation.
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Introduction
Synthetic glucocorticoids are used in a wide variety of disorders, including autoimmune, pulmonary, and gastrointestinal diseases, as well as in patients following organ transplantation and with malignancies. Although the indications for glucocorticoids in these various conditions are clear, their use is fraught with a host of potential side effects. One organ system that has the potential to be profoundly affected by glucocorticoids is the skeleton, and glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis [1]. Despite the fact that glucocorticoids can cause bone loss and fractures, many patients receiving or initiating long-term glucocorticoid therapy are not evaluated for their skeletal health. Furthermore, patients often do not receive specific preventive or therapeutic agents when indicated [2–4]. New knowledge of the pathophysiological mechanisms underlying GIO has been accompanied by the availability of effective strategies to prevent and treat GIO. This article focuses on the cellular aspects of glucocorticoid action in bone, highlighting the mechanisms that are responsible for bone loss (Fig. 1) [5]. We also review current guidelines and therapeutic approaches for the prevention and treatment of GIO.
Direct effects of glucocorticoids on bone cells
Osteoblasts
Glucocorticoids decrease the number and the function of osteoblasts. These effects lead to a suppression of bone formation, a central feature in the pathogenesis of GIO. Glucocorticoids decrease the replication of cells of the osteoblastic lineage, reducing the pool of cells that may differentiate into mature osteoblasts [6, 7]. In addition, glucocorticoids impair osteoblastic differentiation and maturation [5]. Under certain experimental conditions, on the other hand, glucocorticoids have been reported to favor osteoblastic differentiation [8]. In murine models, basal levels of glucocorticoids seem to be required for cortical bone acquisition and osteoblast differentiation [9]. However, the effects of glucocorticoids to favor osteoblast differentiation seem to be highly dependent on experimental conditions, and do not reflect the loss of cells of the osteoblastic lineage regularly seen following glucocorticoid exposure [5].
In the presence of glucocorticoids, bone marrow stromal cells, the precursors of osteoblasts, do not differentiate or are directed, instead, toward cells of the adipocytic lineage [10–12]. Mechanisms involved in this redirection of stromal cells include induction of nuclear factors of the CCAAT enhancer binding protein family and the induction of peroxisome proliferator-activated receptor γ 2 (PPARγ 2), both of which play essential roles in adipogenesis [5, 13, 14]. In accordance with these observations, thiazolidinediones, which are known to activate PPARγ 2, inhibit osteoblastic cell differentiation in murine models. Recent observations in human subjects indicate that diabetic patients receiving thiazolidinediones have a higher incidence of fractures [15].
An additional mechanism by which glucocorticoids inhibit osteoblast cell differentiation is by opposing Wnt/β-catenin signaling [5, 16, 17]. Wnt signaling has emerged as a key regulator of osteoblastogenesis. Wnt uses four known signaling pathways, but in skeletal cells the canonical Wnt/β-catenin signaling pathway operates [18]. In this pathway, when Wnt is absent, β-catenin is phosphorylated by glycogen-synthase kinase-3β (GSK-3β), and then degraded by ubiquitination. When Wnt is present, it binds to specific receptors, called frizzled, and to co-receptors, low density lipoprotein receptor related proteins (LRP)-5 and -6, leading to inhibition of GSK-3β activity. When GSK-3β is not active, stabilized β-catenin translocates to the nucleus, where it associates with transcription factors to regulate gene expression [19]. Deletions of either Wnt or β-catenin result in the absence of osteoblastogenesis, and increased osteoclastogenesis [19, 20]. The Wnt pathway can be inactivated by Dickkopf, an antagonist that prevents Wnt binding to its receptor complex. Glucocorticoids enhance Dickkopf expression and maintain GSK 3-β in an active state, leading ultimately to the inactivation of β-catenin [16, 17, 21].
In addition to inhibiting the differentiation of osteoblasts, glucocorticoids inhibit the function of the differentiated mature cells. Glucocorticoids inhibit osteoblast-driven synthesis of type I collagen, the major component of the bone extracellular matrix, with a consequent decrease in bone matrix available for mineralization [5]. The decrease in type I collagen synthesis occurs by transcriptional and post-transcriptional mechanisms [22].
Glucocorticoids have pro-apoptotic effects on osteoblasts and osteocytes due to activation of caspase 3, a common downstream effector of several apoptotic signaling pathways [23, 24]. Caspases are synthesized as proenzymes and are activated through autocatalysis or a caspase cascade. Active caspases contribute to apoptosis by cleaving target cellular proteins. Caspase 3 is a key mediator of apoptosis and is a common downstream effector of multiple apoptotic signaling pathways [24]. The inhibitory effects of glucocorticoids on osteoblastic cell replication and differentiation and the increased apoptosis of mature osteoblasts, all contribute to the depletion of the osteoblastic cellular pool and decreased bone formation.
Osteocytes
Osteocytes serve as mechanosensors, and play a role in the repair of bone microdamage [25]. Loss of osteocytes disrupts the osteocyte-canalicular network resulting in a failure to detect signals that normally stimulate processes associated with the replacement of damaged bone [26]. Disruption of the osteocyte-canalicular network can disrupt fluid flow within the network adversely affecting the material properties of the surrounding bone, independent of changes in bone remodeling or architecture [26]. Glucocorticoids affect the function of osteocytes, by modifying the elastic modulus surrounding osteocytic lacunae [27]. Glucocorticoids induce the apoptosis of osteocytes [23]. As a result, the normal maintenance of bone through this mechanism is impaired and the biomechanical properties of bone are compromised [27].
Osteoclasts
In human subjects, GIO occurs in two phases: a rapid, early phase in which bone mineral density (BMD) is reduced, presumably due to excessive bone resorption, and a slower, progressive phase in which BMD declines due to impaired bone formation [28]. Osteoclasts are members of the monocyte/macrophage family of cells that differentiate under the influence of two requisite cytokines, namely macrophage colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANK-L) [29]. Glucocorticoids increase the expression of M-CSF and RANK-L, and decrease the expression of its soluble decoy receptor, osteoprotegerin, in stromal and osteoblastic cells [30, 31]. Glucocorticoids also enhance the expression of Interleukin-6, an osteoclastogenic cytokine, and suppress the expression of interferon-beta, an inhibitor of osteoclastogenesis [32, 33]. Glucocorticoids decrease the apoptosis of mature osteoclasts [34]. Consequently, there is increased formation of osteoclasts with a prolonged life span explaining, at the cellular level, the enhanced and prolonged bone resorption observed in GIO. The direct effects of glucocorticoids on osteoclasts also may contribute to an operational decline in osteoblast function during glucocorticoid exposure [35]. Although the net effect of glucocorticoids is to enhance osteoclast number, osteoclast function may be tempered with cells that no longer spread and resorb mineralized matrix normally. Osteoblast signals that depend upon normal osteoclast function could, thus, be impaired [35]. However, these novel findings have been challenged by studies demonstrating a primary effect of glucocorticoids on cells of the osteoblastic lineage [34]. In accordance with their effects on bone resorption, glucocorticoids enhance the expression of selected matrix metalloproteinases (MMP). Osteoblasts secrete MMP1 or collagenase 1 and MMP13 or collagenase 3, and both cleave type I collagen fibrils at neutral pH [36, 37]. Cortisol increases collagenase 3 synthesis by post-transcriptional mechanisms, by regulating specific cytosolic RNA binding proteins, and their binding to specific RNA sequences [38]. Glucocorticoids may also have effects on bone remodelling at the basic multicellular unit (BMU) level, mainly manifested as a reduction in wall width (reduced amount of bone formed per BMU) [39, 40]. In addition, there is some evidence that increased resorption depth (increased amount of bone resorbed per BMU) may occur in the early stages of therapy, particularly at high doses of glucocorticoids.
Effects of glucocorticoids on bone cells mediated by growth factors
In addition to the direct actions of glucocorticoids on bone target cells, other effects are mediated by changes in the synthesis, receptor binding or binding proteins of growth factors present in the bone microenvironment. Glucocorticoids influence the expression of insulin-like growth factor (IGF) I. IGF-I increases bone formation and the synthesis of type I collagen, and decreases bone collagen degradation and osteoblast apoptosis [41]. Glucocorticoids suppress IGF I gene transcription, but do not alter IGF I receptor number or affinity in osteoblasts [5]. Glucocorticoids decrease IGF II receptor number, but the skeletal functions of the IGF II receptor have remained elusive [42]. The activities of IGFs are regulated by six IGF binding proteins (IGFBP), all of which are expressed by the osteoblast [43]. Of these, IGFBP-5 was reported to have anabolic effects for skeletal cells, and its transcription is suppressed by glucocorticoids [44]. The inhibition of IGFBP-5 synthesis by glucocorticoids is probably not key to the ultimate effect of glucocorticoids on osteoblastic function, because transgenic mice overexpressing IGFBP-5 exhibit decreased, and not increased bone formation [45]. The effects of glucocorticoids on IGF-I expression by the osteoblast are reversed by parathyroid hormone (PTH), an observation that may help explain why PTH may be effective in the treatment of GIO [46].
Indirect effects of glucocorticoids on bone metabolism
Glucocorticoids inhibit calcium absorption from the gastrointestinal tract, by opposing vitamin D actions, and by decreasing the expression of specific calcium channels in the duodenum [47]. Renal tubular calcium reabsorption also is inhibited by glucocorticoids [1]. As a consequence of these effects, secondary hyperparathyroidism could exist in the context of glucocorticoid use. But a hyperparathyroid state does not explain the bone disorder observed in GIO. Most patients with GIO do not exhibit serum levels of PTH that are frankly elevated. Although vertebral and non-vertebral fractures occur in GIO, this condition is associated with a preferential loss of cancellous bone, whereas hyperparathyroidism, is associated with a preferential loss of cortical bone [48, 49]. Moreover, bone histomorphometric analysis demonstrates reduced bone turnover in GIO, in contrast to the increased bone turnover that characterizes hyperparathyroidism [1, 28]. These observations indicate that hyperparathyroidism does not play a central role in the development of the skeletal manifestations of GIO. Nevertheless, there may be subtle, but important effects of glucocorticoids on the secretory dynamics of PTH, with a decrease in the tonic release of PTH and an increase in pulsatile bursts of the hormone [50]. In healthy subjects, PTH is secreted by low amplitude and high frequency pulses superimposed upon tonic secretion. Pulsatile PTH secretion may be important for the regulation of the actions of the hormone on bone [51]. Abnormal PTH pulsatility is found not only following glucocorticoid exposure, but also in post-menopausal women and in acromegaly [52, 53]. Additionally, glucocorticoids may enhance the sensitivity of skeletal cells to PTH, by increasing the number and affinity of PTH receptors [54].
In addition to the direct effects of glucorticoids on skeletal IGF-I, glucocorticoids decrease the secretion of growth hormone (GH) and may alter the systemic GH/IGF-I axis [55]. However, serum levels of IGF-I are normal in GIO. GH secretion is blunted by glucocorticoids by an increase in hypothalamic somatostatin tone, and GH administration could reverse some of the negative effects of chronic glucocorticoid treatment on bone [56–58]. Secretion of GH is blunted in asthmatic patients receiving inhaled corticosteroids, suggesting that inhaled steroids may alter the synthesis or release of GH [59]. However, the cause or consequence of this effect is not clear, since serum levels of cortisol and of IGF-I are not suppressed [59]. Glucocorticoids inhibit the release of gonadotropins, and as a result estrogen and testosterone production. This effect of glucocorticoids on the gonadal axis may be an additional factor playing a role in the pathogenesis of GIO [60].
Pathogenesis of fractures in GIO
Fractures may occur in as many as 30–50% of patients receiving chronic glucocorticoid therapy [61–63]. They occur more frequently in postmenopausal women and men at sites enriched in cancellous bone, such as the vertebrae and femoral neck [64, 65]. As with vertebral fractures occurring in post-menopausal osteoporosis, vertebral fractures associated with glucocorticoid therapy often are asymptomatic [63]. When assessed by X-ray-based morphometric measurements of vertebral bodies, 37% of postmenopausal women on chronic (> 6 months) oral glucocorticoid therapy sustain one or more vertebral fractures [63]. Vertebral fractures occur early after exposure to glucocorticoids, at a time when BMD declines rapidly [66]. The early rapid loss of bone predisposes to fracture, even in individuals whose T-scores are only in the osteopenic range.
Although fractures can occur early in the course of glucocorticoid therapy, their incidence is also related to the dose and duration of glucocorticoid exposure. Doses as low as 2.5 to 7.5 mg of prednisolone equivalents per day can be associated with a 2.5-fold increase in vertebral fractures, but the risk is greater at higher doses for prolonged periods of time [1, 67]. Following the exposure to prednisone equivalents of 10 mg daily for longer than 90 days, the risk of fractures of the hip and spine is increased by 7- and 17-fold, respectively [67]. The risk of fracture declines after discontinuation of glucocorticoid therapy [1].
The reason for the individual heterogeneity in the response to glucocorticoids is not known, but differential responses may be associated with polymorphisms of the glucocorticoid receptor gene. Glucocorticoid receptor polymorphisms are associated with differences in BMD and body composition [68–70]. Indeed, body composition and risk of fracture during glucocorticoid treatment seem to be closely related [71]. Another explanation for individual variability in the response of patients exposed to glucocorticoids is related to peripheral enzymes that interconvert active and inactive glucocorticoid molecules. 11β-hydroxysteroid dehydrogenases regulate the interconversion between cortisone and hormonally active cortisol, and play a role in the regulation of glucocorticoid activity [72]. Two 11β-hydroxysteroid dehydrogenase enzymes have been described: 11β-hydroxysteroid dehydrogenase type-1 is primarily a glucocorticoid activator, converting cortisone to cortisol, and 11β-hydroxysteroid dehydrogenase type II is an inhibitor enzyme expressed in mineralocorticoid target tissues. The type I enzyme is widely expressed in glucocorticoid target tissues, including bone, and its activity and the potential to generate cortisol from cortisone in human osteoblasts is increased by glucocorticoids [72–75]. There seems to be an inverse relationship between 11β-hydroxysteriod dehydrogenase type I activity and osteoblast differentiation [75]. An increase of 11β-hydroxysteriod dehydrogenase type I activity occurs with aging, possibly providing an explanation for the enhanced sensitivity of the elderly to the effects of glucocorticoids on the skeleton [75].
An important point that is often minimized in discussions about GIO is that many disorders for which the glucocorticoids are prescribed are themselves causes of osteoporosis. One has to take into account, therefore, the underlying disease itself along with the use of glucocorticoids when considering the management of GIO. Inflammatory bowel disease, rheumatoid arthritis and chronic obstructive pulmonary disease (COPD), for example, all are associated with bone loss, independent of glucocorticoid treatment [76, 77]. The systemic release of inflammatory cytokines, which affect bone formation and bone resorption seem to underlie the pathophysiology of the bone loss in these settings [76, 77]. However, there are additional factors that may play a role in the bone loss. In inflammatory bowel disease, bone loss may be due, in part, to malabsorption of vitamin D, calcium and other nutrients [76]. In COPD, hypoxia, acidosis, reduced physical activity, and smoking may all contribute to bone loss, independent of the use of glucocorticoids [60, 78, 79].
A direct relationship between BMD and fracture risk in GIO has not been established [80–82]. It is likely to be different from that established in postmenopausal osteoporosis because fractures in GIO occur at higher BMDs [83] (Fig. 2). This point has to be considered when making treatment decisions in GIO. The Royal College of Physicians recommends a vertebral T-score of −1.5 as the intervention threshold. The American College of Rheumatology (ACR) recommends a more stringent therapeutic intervention at a T-score of ≤ −1. These scores are higher than the treatment threshold T-Scores of −2.0 to −2.5, often used in the management guidelines for post-menopausal osteoporosis [84]. The reasons for the altered relationship between BMD and risk of fracture are complex [85, 86]. In addition to the rapid decline in BMD that occurs following glucocorticoid exposure (the faster the bone loss, the greater the risk), other factors influence bone strength and fracture risk in GIO. These include the underlying disease for which patients receive glucocorticoids, and multiple cellular events that lead to structural changes in bone [87]. In GIO, the negative effects of glucocorticoids on osteoblasts and osteocytes affect adversely the architecture of cancellous bone. However, these changes often are not translated into a decrease in BMD. Reductions in trabecular thickness, number, and connectivity cannot be determined by currently available non-invasive imaging modalities. Newer technologies, such as high resolution peripheral quantitative computed tomography or micro magnetic resonance imaging may be helpful in identifying individual fracture risk of patients on glucocorticoids [88].
Although biochemical markers of bone turnover can be useful measures of bone remodeling activity and can predict fracture risk, their value in GIO has not been established and their levels vary with the stage of the disease [89]. Following the initial exposure to glucocorticoids, there is an increase in biochemical markers of bone resorption, which is followed by a suppression of markers of bone formation and bone resorption [89].
In addition to the direct effects of glucocorticoids on bone cells, the catabolic effects of glucocorticoids on muscle may contribute to fracture risk since these steroids cause muscular weakness, which can increase the incidence of falls. Glucocorticoid-induced myopathy may occur following early exposure to glucocorticoids [90]. Chronic glucocorticoid-induced myopathy is generally manifested by weakness particularly of the pelvic girdle musculature and may affect up to 60% of patients treated with glucocorticoids [60]. The myopathy involves muscle loss due to glucocorticoid induced proteolysis of myofibrils [91]. This is mediated by activation of lysosomal and ubiquitin-proteasome enzymes. Recent studies have demonstrated that glucocorticoids induce myostatin, a negative regulator of muscle mass. Deletion of the myostatin gene prevents glucocorticoid induced myofibril proteolysis and muscle loss in murine models [91]. This would suggest that myostatin plays a role in the mechanism of muscular atrophy in GIO.
Management of GIO
Guidelines
ACR and the Royal College of Physicians have proposed primary prevention and treatment guidelines. Primary prevention is intervention with a bone-sparing agent at the initiation of (or very soon after) commencement of glucocorticoid therapy. Secondary prevention is initiation of bone protective medication in patients already established on glucocorticoid therapy (Table 1). The guidelines advocate the following measures for the prevention and treatment of GIO: general health awareness, administration of sufficient calcium and vitamin D, reduction of the dose of glucocorticoids to a minimum and, when indicated, therapeutic intervention with bisphosphonates and possibly other agents [92]. UK guidelines recommend primary prevention in all men and women over the age of 65 years, in individuals with a history of previous fractures and in younger people with BMD T scores of ≤ − 1.5, who are committed to at least 3 months of oral glucocorticoid therapy at any dose (Table 1). ACR recommends preventive measures in patients exposed to glucocorticoids for longer than 3 months (5 mg prednisone equivalent, or higher, daily), including lifestyle changes, such as tobacco cessation and reduction of alcohol consumption, an exercise program, restriction of sodium intake in the presence of hypercalciuria, sufficient calcium intake and adequate vitamin D supplementation. ACR guidelines recommend that treatment with bisphosphonates should be started in these subjects if their T-score is ≤ −1.0, as assessed by vertebral densitometry [84, 92]. Table 1 shows similarities and differences between ACR and UK guidelines [84].
Specific therapeutic approaches
Vitamin D plays an important adjuvant role in the management of GIO [93–97]. Vitamin D increases the intestinal absorption of calcium and reabsorption of calcium in the distal renal tubules. In addition to its role in calcium homeostasis, vitamin D plays a function in the maintenance of muscular strength and balance. A practical consideration regarding vitamin D therapy in subjects receiving glucocorticoids, relates to vitamin D resistance that occurs in this setting. Rather than maintaining 25-hydroxyvitamin D levels at an adequate level of 30 ng/ml (82 nmoles/L), some experts recommend that the goal be set at higher serum levels of 25 hydroxyvitamin D of ≥ 80 nmol/L. In order to maintain these levels, patients often require amounts of 1,000–2,000 International Units of vitamin D daily [98].
Bisphosphonates are considered to be the pharmacologic gold standard for the prevention and treatment of GIO [84, 99]. The benefits of bisphosphonates in GIO have been ascribed to their anti-resorptive effect. Bisphosphonates are more effective than vitamin D in the prevention of bone loss and fractures in GIO, but should be given with supplemental calcium and vitamin D [100]. The primary end-point of bisphosphonate trials has been the stabilization or the increase of BMD, with fracture outcomes as secondary end points. In selected trials, bisphosphonates were shown to decrease the incidence of vertebral fractures in GIO [61, 62, 101–103]. It is advisable to continue bisphosphonates for the duration of glucocorticoid treatment. This recommendation is consistent with data demonstrating that fracture risk is highest during the time of glucocorticoid exposure [104]. The use of bisphosphonates in women of childbearing age has to be carefully considered, since bisphosphonates have a prolonged half life, and they can cross the placenta with potential unwanted effects on fetal skeletal development.
In postmenopausal women, estrogens preserve bone mass whether in the context, or not, of glucocorticoid exposure, and they can be a treatment option [105]. However, the use of estrogens has to be carefully considered because of unwanted adverse effects.
An anabolic approach to the treatment of GIO might have promise since the disorder is primarily one of reduced bone formation. PTH is an attractive candidate because it induces skeletal IGF I and inhibits osteoblast apoptosis, increasing osteoblast cell number [36, 106–108]. The use of PTH in GIO has been examined in postmenopausal women with rheumatoid arthritis treated with prednisone and estrogen replacement [109, 110]. In this population, daily treatment with hPTH (1–34) increased vertebral BMD. Modest increases in bone mass were observed at the hip. PTH administration induces an initial uncoupling of bone remodeling with an early increase in bone formation followed by a more gradual increase of bone resorption [111]. According to the concept of the “anabolic window”, PTH rapidly and powerfully stimulates osteoblast function [112]. PTH is currently being tested in clinical trials to determine its efficacy in GIO.
Conclusions
GIO is a serious skeletal disorder that is associated with fractures. New knowledge of mechanisms of glucocorticoid action has demonstrated detrimental effects on osteoblast and osteocyte function, and prolonged osteoclast life span. The extent and rate of bone loss determine the risk of fractures. GIO can be prevented and treated with bisphosphonates. Future therapies may include the use of PTH and other anabolic agents.
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This work was supported by Grant AR21707 (E. Canalis) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Grants DK42424 and DK45227 (E. Canalis), and DK32333 (J.P. Bilezikian) from the National Institute of Diabetes & Digestive & Kidney Diseases and by MIUR and Centro di Ricerca sull’Osteoporosi-University of Brescia/EULO (A. Giustina).
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Canalis, E., Mazziotti, G., Giustina, A. et al. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 18, 1319–1328 (2007). https://doi.org/10.1007/s00198-007-0394-0
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DOI: https://doi.org/10.1007/s00198-007-0394-0