Clinical Reviews in Bone and Mineral Metabolism

, Volume 8, Issue 1, pp 15–26

Glucocorticoid-Induced Osteoporosis: A Review

Authors

  • Béatrice Bouvard
    • Faculté de MédecineINSERM, U 922–LHEA
    • Service de Rhumatologie
  • Erick Legrand
    • Faculté de MédecineINSERM, U 922–LHEA
    • Service de Rhumatologie
  • Maurice Audran
    • Faculté de MédecineINSERM, U 922–LHEA
    • Service de Rhumatologie
    • Faculté de MédecineINSERM, U 922–LHEA
Original Paper

DOI: 10.1007/s12018-009-9051-9

Cite this article as:
Bouvard, B., Legrand, E., Audran, M. et al. Clinic Rev Bone Miner Metab (2010) 8: 15. doi:10.1007/s12018-009-9051-9

Abstract

Glucocorticoid (GC)-induced osteoporosis is the main cause of secondary osteoporosis. Fractures, which are often asymptomatic, can occur in as many as 50% of patients receiving chronic GC therapy. GCs have direct and indirect effects on bone cells (osteoblasts, osteocytes, and osteoclasts) with a suppression of bone formation and an increased bone resorption. The management of patients exposed to GCs should include the use of the minimal effective dose of GC, general health measures, and adequate intakes of calcium and vitamin D. Bisphosphonates are nowadays largely used in GC-induced osteoporosis and teriparatide has proved its efficiency as well.

Keywords

Glucocorticoid-induced osteoporosisFracturesBone mineral densityMicroarchitectureBone formationBone resorptionBisphosphonates

Introduction

The deleterious effects of prolonged exposure to an excess of cortisol on the skeleton were first recognized and described by Cushing in 1932 [1]. The inactive form of the glucocorticoid (GC) cortisol, so-called cortisone, was isolated in the years 1936–1940 by different groups, and cortisol was first synthesized by Reichstein in 1939 [2, 3]. About 10 years later, GCs were introduced into clinical medicine and the researchers primarily involved, Kendall, Hench, and Reichstein, won the Nobel Prize for Physiology or Medicine in 1950 for research on the structure and biological effects of adrenal cortex hormones. The new GCs prednisolone and methylprednisolone were synthesized in the years 1950–1960 with stronger anti-inflammatory and immunosuppressive potencies, and lesser mineralocorticoid activities [4]. Synthetic GCs are used in a wide variety of disorders including autoimmune, pulmonary, rheumatologic, and gastrointestinal diseases, malignancies as well as in organ transplantation. Although the indications for GCs in these various conditions are clear, their use is complicated by potential side effects in particular on the skeleton (Tables 1 and 2); GC-induced osteoporosis (GIOP) being the most common cause of secondary osteoporosis. Despite the evidence that GCs can cause bone loss and fractures, many patients receiving or initiating a long-term GC therapy are still nowadays not evaluated for skeletal health. Furthermore, patients often do not receive specific preventive or therapeutic agents when indicated. GCs have other deleterious effects on various systems: sodium metabolism, lipids, skin, muscle, and immune response which can interact with bone metabolism [5]. In addition, there is an individual variation in susceptibility to develop GIOP and this type of osteoporosis is complicated by the underlying disease, which often constitutes a risk of osteoporosis in itself. In this article, we will review the effects of GCs at the molecular, cellular, and tissular levels in the skeleton. The use of animal models to analyze the pathophysiological mechanisms will be presented and the different therapeutic approaches will be considered.
Table 1

Tissular effects of GCs

Tissue

Effects

Endocrine disease

Hypothyroidism and hypogonadism, menstrual irregularity

Cardiovascular disease

Dyslipemia, hypertension, thrombosis

Metabolic syndrome

Combination of visceral obesity, systemic arterial hypertension, impairment of glucose tolerance, and/or dyslipemia. Hyperphagia and weight gain

Auto-immunity

Involution of lymphoid tissue mass and lymphopenia

Increase susceptibility to infectious diseases

Skin

Hirsutism, acne, easy bruising, centripetal obesity, moon facies, buffalo hump, supraclavicular fat pads, and violaceous abdominal striae, lipodystrophy, altered wound healing

Kidney

Nephrolithiasis and impairment of renal clearance, hypercalciuria, hyperuricosuria, increased urinary levels of oxalate, and decreased urinary levels of citrate

Central nervous system

Intellective deficiency, psychological impairment, anxiety, depression, atrophy of specific cerebral areas

Eye

Cataract, glaucoma

Visceral manifestations

Pancreatitis, epigastric pain

Others

Hand tremors

Table 2

Direct and indirect effects of GCs on bone

Tissue

Effects

Bone

↓ bone formation, ↑ bone resorption

    Osteoblast

↓ differentiation and function

 

↑ apoptosis

    Osteocyte

↑ apoptosis

    Osteoclast

↑ span life

Muscle

Muscular weakness, proteolysis of myofibrils

↑ myostatin, muscle cramps

Neuroendocrine system

↓ sex steroids, ↓ LH pulse frequency

↓ GH/IGF-I

Calcium metabolism

↓ intestinal absorption

↑ renal excretion

LH luteinizing hormone, GH growth hormone, IGF-I Insulin-like growth factor 1

Molecular Effects of GCs

The GC Receptor

In bone cells, cellular effects of GCs are primarily mediated by the GC receptor which is a member of the nuclear receptor superfamily. In the absence of ligand, the receptor is retained in the cytosol (cGCR) as part of a chaperone-containing multiprotein complex [6]. The human cGCR gene, located at chromosome 5q31.3, is widely expressed in a number of bone cells including osteoblasts (OB), osteocytes, and chondrocytes [7]. The GCR transcripts are also detected in stromal-like tumor cells, macrophage-like cells [putative osteoclast (OC) precursor], and multinucleated osteoclast-like cells [8]. Different studies have suggested that the polymorphism of the cGCR gene is correlated with bone mineral density (BMD) variation and may explain the heterogeneity to GC-associated bone loss and fractures [911].

Upon hormone binding, cGCR translocates to the nucleus, where it acts as a transcription factor. The cGCR subunits homodimerize and bind DNA at GC response elements (GREs) in the vicinity of target genes. The process which is mediated through positive GREs is named transactivaction and induces synthesis of anti-inflammatory proteins such as lipocortin 1, IκB and is also thought to be responsible for numerous side effects of GCs [4, 12, 13] (Table 3, Fig. 1a). On the other hand, transcription of genes can be inhibited by GCs by a direct interaction between the GC/GCR complex and negative GREs [14, 15] or by an interaction of monomers of GC/GCR complex with transcription factors. In this last mechanism, named transrepression, GCs inhibit nuclear translocation and the function of several pro-inflammatory transcription factors such as nuclear factor-κB or activator protein 1 and suppress synthesis of inflammatory mediators such as tumor necrosis factor-α (TNF-α), INF-γ, IL-1, and IL-2 (Fig. 1b). More than 3 min are needed for a genomic effect and hours or days before changes at the cell, tissue, or organism level become evident. However, some of the immunosuppressive, anti-inflammatory, and anti-allergic GC effects occur too fast to be explained by such genomic mechanisms of GC. Three different non-genomic mechanisms have been proposed to explain rapid anti-inflammatory and immunosuppressive GC effects: non-specific interactions of GCs with cell membranes, non-genomic effects mediated by the cGCR, and specific interactions with a membrane-bound GCR [4, 12, 16].
Table 3

Molecular effects of glucocorticoids

Genomic mechanisms

Transcription

Transactivaction: synthesis of anti-inflammatory proteins through positive GREs (lipocortin 1, IκB)

Suppression of transcription of inflammatory genes through negative GREs

Transcription inhibition

Transrepression: monomers of GC/GCR complex interact with transcription factors which are involved in regulating expression of pro-inflammatory genes (AP-1, NF-κB) thereby suppressing synthesis of inflammatory cytokines (IL-1, IL-2, TNF-α, IFN-γ)

Competition for nuclear coactivators between the GC/cGCR complex and transcription factors

Non-genomic mechanisms

 

Interactions of GC with cellular membranes

Non-genomic effects mediated by the cGCR

Specific interactions with a membrane-bound GCR

GC glucocorticoid, cGCR cytosolic glucocorticoid receptor, GREs glucocorticoid response elements, AP-1 activator protein 1, NF-κB nuclear factor-κB

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Fig. 1

Genomic mechanisms of GC action. aTransactivation: the ligand-activated cytosolic GC receptor (cGR) translocates into the nucleus where it binds as a homodimer to positive GREs inducing the synthesis of anti-inflammatory proteins (e.g., lipocortin 1, IκB). bTransrepression: monomer of GC/cGR complex interact with transactivation factors such as NFκB which are involved in regulating the expression of pro-inflammatory genes (TNF-α, IL-1)

11β-Hydroxysteroid Dehydrogenase

Tissue responses to GCs are partly determined at a prereceptor level through expression of the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSDs), which catalyze the interconversion of the hormonally inactive cortisone into active cortisol [1719]. Two isozymes, 11β-HSD1 and 11β-HSD2, have been shown to regulate GC and mineralocorticoid hormone action. 11β-HSD1 acts predominantly as a reductase converting inactive cortisone to active cortisol. In contrast, 11β-HSD2 inactivates cortisol to cortisone. 11β-HSD1 transcripts are increased by GCs and agents that block 11β-HSD1 in bone may reduce GC effects on bone [20]. IL-1 and TNF-α inhibit the expression of 11β-HSD2 and induce mRNA expression and activity of 11β-HSD1 in human OB, suggesting that IL-1 and TNF-α may sensitize skeletal tissue to the action of GC [21]. Variation in 11β-HSD isoenzyme expression and activity may explain individual susceptibility to GIOP.

Cellular Effects of GCs

Bone has a continuous and dynamic turnover with successive cycles of resorption and renewal of bone packets as a consequence of the coupled action of bone-resorbing cells, OC and bone-forming cells, OB. In normal adult bone, the processes of resorption and formation are coupled in both space and time and the amount of bone resorbed and formed is at the equilibrium. In GIOP, in vivo data indicate that GCs stimulate bone resorption and decrease bone formation, resulting in bone loss. GCs exert complex effects on the skeleton, either inhibiting or enhancing, which are dependant on the species under investigation, the developmental stage as well as the concentration and duration of GC exposure [22]. In vitro, a low concentration of GCs induces cells of the osteoblast lineage to differentiate into mature OBs [2328], whereas GCs at high concentrations dramatically decrease OB number and bone formation rate [2931]. Interaction of GCs with other factors/hormones, such as cytokines in inflammatory diseases, might be important in vivo and several secondary effects of GC treatment could major the role of GCs on bone [22]. Mechanisms by which GCs cause osteoporosis are multiple and include direct and indirect effects on OBs and OCs (Table 4).
Table 4

Cellular effects of GCs

Cell

Effects

Mechanisms

Osteoblast

↓ differentiation

Induction of the adipogenetic transcription factors (PPARγ and CCAAT enhancer binding protein family)

Opposing Wnt/β-catenin signaling pathway: ↑ Dkk-1 ↑ SFRP1, ↓ PI3K/Akt/GSK3beta/beta-catenin/LEF axis and ↑ histone deacetylase 1

↓ BMP-2

↓ Krox 20

↑ MKP-1 and Notch-1

↓ function

↓ GH

↓ synthesis and function of IGF-I

↓ type I collagen synthesis

↓ synthesis of IGFBP-3, -4 and -5 and ↑ IGFBP-6

↑ collagenases 1 and 3

↑ apoptosis

↑ caspase 3, ↑ Bim, ↓ Bcl-2/Bax

Osteocyte

↑ apoptosis

↑ caspase 3, ↑ Bim, ↓ Bcl-2/Bax

Reduction in the elastic modulus and mineral to matrix ratio around the osteocyte lacuna

Osteoclast

 

↑ M-CSF, RANK-L, ↓ osteoprotegerin

↓ IRAK-M

↑ IL-6, ↓ IFN-β

Impact on the cytoskeleton

PPARγ peroxysome proliferator-activated receptor γ, CCAAT, Dkk-1 Dickkopf-1

Effects of GCs on OB Function

GCs reduce the expression of insulin-like growth factors (IGF) I and II known to increase OB differentiation [32, 33], type I collagen synthesis, and bone formation, and increase bone collagen degradation by decreasing the synthesis of collagenases 1 and 3 [34]. GCs also reduce the expression of non-collagenous proteins such as osteocalcin, osteopontin, bone alkaline phosphatase, and tissue inhibitor of metalloproteinase 1 [25, 35].

GCs also inhibit the synthesis of IGFBP-3, -4, and -5 (which are binding proteins that can stimulate bone cell growth) and increase the expression of IGFBP-6 (a binding protein that selectively blocks the effects of IGF-II on OBs) [36]. Taken together, these effects induce a marked reduction in the number of OBs and in their capacity to synthesize bone matrix.

In vivo and in vitro studies indicate that GCs favor the differentiation of bone marrow stromal cells toward the adipocytic pathway by the induction of the adipogenetic transcription factors (PPARγ and CCAAT enhancer binding protein family). This may occur at the expense of OB cell differentiation [3740]. GCs also inhibit OB differentiation by opposing Wnt/β-catenin signaling, a key regulator of osteoblastogenesis. In the absence of the Wnt protein, β-catenin is phosphorylated by glycogen-synthase kinase-3β (GSK-3β), and then degraded by ubiquitination. In the presence of Wnt, the protein binds to frizzled receptors and then to the co-receptors LRP-5 or LRP-6 (low-density lipoprotein receptor-related proteins) leading to inhibition of GSK-3β activity. When GSK-3β is not active, β-catenin is stabilized and translocates to the nucleus, where it associates with transcription factors to regulate gene expression. Deletions of either Wnt or β-catenin result in the absence of osteoblastogenesis and increased osteoclastogenesis. The Wnt pathway can be inactivated by Dickkopf-1 (Dkk-1), an antagonist that prevents Wnt binding to its receptor complex. Dexamethasone (Dex) markedly induces the expression of Dkk-1 mRNA in cultured human OB [41]. The addition of anti-Dkk-1 antibodies partially restores the transcriptional activity suppressed by Dex [42]; in contrast knocking down Dkk-1 expression in bone tissue abrogates GC impairment of osteogenic activities, microarchitecture, and bone mass [43]. Furthermore, a supraphysiological level of GC can enhance SFRP-1 expression, another antagonist of the Wnt/β-catenin signaling pathway; knocking down SFRP1 abrogates this effect [44, 45]. GCs also inhibit osteoblast differentiation through the repression of growth hormone (GH) and bone morphogenic protein 2 (BMP-2) which enhances OB transcription factors [32]. Other less known mechanisms have been identified to explain the impact of GCs on OB differentiation involving Krox 20/EGR2 [46], MPK-1 [47], Notch [48], and the TGF-β-Smad pathway [49].

Apoptosis of Cell of the Osteoblastic Lineage

GCs have pro-apoptotic effects on OBs and osteocytes due to the activation of caspase-3, a key mediator of multiple apoptotic signaling pathway [50] and Bim whose expression occurs prior to activation of caspase 3 [51]. GCs also regulate the expression of Bax and Bcl-2 inducing downregulation of Bcl-2 and/or upregulation of Bax (reduced Bcl-2/BAX ratio) involving in apoptosis [52, 53] (Fig. 2).
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Fig. 2

GCs induce apoptosis of cells of the osteoblastic lineage. Apoptotic cells are identified using immuno histochemical detection of caspase-3 activity (hematoxylin counterstain), original magnification ×200 a Apoptotic OB lining the trabecular surface. The antigen retrieval treatment is responsible for the detachment from the trabecular surface. Nucleus (arrow), cytoplasm with dense particles corresponding to anti-caspase 3 activity (arrowhead). b Control osteocytes (arrow) without labeling. c An apoptotic osteocyte inside lacunae in mineralized bone. Nucleus (arrow), cytoplasm with a dark labeling corresponding to anti-caspase 3 activity (arrowhead)

Effects of GCs on Bone Resorption

In vitro, GCs increase the expression of M-CSF [54] and RANK-L [13, 55] in stromal and OBs (two cytokines involved in OC differentiation), and decrease osteoprotegerin expression (the soluble decoy receptor of RANK-L) [56, 57]. In vivo, GCs act directly on OCs to delay apoptosis of mature cells explaining the enhanced and prolonged bone resorption observed in GIOP [58, 59]. However, GCs seem to decrease their resorption capacities by disturbing cytoskeleton organization [58].

Tissular Effects of GCs

Bone Histomorphometry and Microarchitecture

The common finding in all histomorphometric studies is a reduction in bone volume (BV/TV) [60]. The reduction in OB number and function induced by GCs leads to a decrease in bone matrix synthesis: this is evidenced by a marked reduction of osteoid parameters, a thinning of trabecular packets [61], and a reduction of the mineral apposition rates (Fig. 3). Evaluation of microarchitectural bone changes was done in a series of iliac biopsies performed in asthmatic male patients with a long-term GC treatment [62]. BV was reduced; trabeculae were thinner but remained well connected until BV/TV reached a threshold of 11%, which was associated with considerable microarchitectural deterioration due to trabecular perforations. They occur when trabecular thickness was below 70 μm, a condition related to OCs which erode bone down to 40 μm in depth [61]. Microcomputed tomography showed a progressive thinning of trabecular plates, maximum at their center where minute perforated areas were observed [63] (Fig. 4). An increased cortical porosity is observed in patients treated with GCs due to significantly more numerous Haversian canals rather than an enlargement of their mean diameter [64]. However, a reduction in cortical thickness is reported in patients with chronic active hepatitis who developed GIOP [65].
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Fig. 3

The depressed osteoblastic activity caused by GC is evidenced by a reduction in the mineral apposition measured after double calcein labeling in the mouse. Labeling with calcein is viewed under UV light, original magnification ×400 a Double regular labels along trabeculae in a control mouse without GC (arrow). b single label and reduced mineralizing surfaces in a GC-treated mouse (arrows)

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Fig. 4

Microcomputed tomography analysis of the transiliac bone biopsy from a patient with GIOP. Thinning of the trabecular plates is associated with perforated areas at their center (arrows)

BMD and Fractures

Synthetic GCs are widely used in clinical practice [66]. Since the osteopenic effects of GCs are greater in trabecular than in cortical bone, bone loss especially affects the axial skeleton (vertebral bodies, pelvis, and ribs). Strong correlations have been found between the cumulative GC dose and the reduction in spine and hip BMDs [6772]. The onset of bone loss is rapid, within the first months of starting GC therapy and slows down after about 1 year of treatment, while remaining higher than normal [73, 74]. In GCs-treated patients, the underlying disease (such as rheumatologic diseases, chronic pulmonary disorders, inflammatory bowel diseases, or post-transplantation status) also constitutes a risk of osteoporosis by itself [7578].

The use of GCs significantly increases the risk of any fracture at all ages [79]. It is estimated that as many as 50% of patients requiring long-term GCs (>3 months) will ultimately suffer from fractures [80, 81]. The risk of fracture starts rapidly after the onset of GC treatment and even low doses of GCs are able to induce fractures. For the same BMD level, the risk of all fractures is substantially greater in GIOP than in post-menopausal osteoporosis [82], with an increased incidence of asymptomatic vertebral fractures [83]. Therefore, GC may have an effect on bone quality that leads to an increased risk of fracture. The different pharmacological types of GCs do not induce the same risk of fracture: oral GCs (such as prednisolone or prednisone) are more potent than hydrocortisone and are associated with a dose-dependent increase in the overall fracture risk. No increase in fracture risk seems to be associated with corticosteroids used as intra-articular or local use. The effect of inhaled GCs on vertebral fractures risk remains controversial. No bone loss is associated with inhaled corticosteroids, except at daily dosages above 7.5 mg of prednisolone (equivalent to 1875 μg of budesonide or beclomethasone) [8486]. Furthermore, there is no evidence that long-term treatment of children with inhaled GCs at low doses is associated with a reduction in BMD or with an increased risk of osteoporosis or fracture [87, 88]. Current evidence shows that treatment with inhaled corticosteroids (medium or high doses) can delay growth rate at the start of treatment with beclomethasone or budesonide. However, this is transitory, since the adult height reached by asthmatic children with inhaled corticosteroids treatment is not different than that reached by non-asthmatic children [89]. The excess risk of fracture (mainly vertebral fractures) seems to return to baseline values within 1 year after withdrawal of GCs [73, 86].

The effects of GCs on bone metabolism are reflected in marked changes in biochemical markers of bone turnover [9092]. Markers of bone formation such as serum osteocalcin fall within a few hours of treatment and parallel the GC dose. Results for bone resorption markers are more variable: they depend on the marker used and their evolution upon time is variable [56, 93, 94].

Others Actions of GCs (Table 2)

In addition to the direct effects of GCs on bone cells, the catabolic effects of GCs on muscle may contribute to fracture risk by inducing muscular weakness which, in turn, increases the incidence of falls [95]. Reduction of gonadal hormones is also an important mechanism through the inhibitory effects of GCs on pituitary gonadotropins [96]. GCs also inhibit calcium absorption in the gastrointestinal tract because of a secondary resistance to vitamin D and enhance urinary loss of calcium. Despite the decrease in serum calcium, hyperparathyroidism does not appear nowadays to be a determinant of bone resorption or skeletal loss in acute or chronic use of GCs [34].

Experimental Models of GIOP

Different animal models have been proposed to study the pathophysiology of GIOP. Contradictory findings have been reported after experimental GC administration to rats that may result from variations in background factors such as the age of the animals or the dose of GC. Murine models are most frequently employed and results appear more consistent. Mice used are usually 5 or 6-month-old, which correspond to the peak bone mass. It has been reported [30] that continuous GC administration with slow release pellets for 27 days (a period equivalent in the mouse to ~3–4 years in humans) decreases the number of OB and OC progenitors, decreases OB and OC surface, and increases OB and osteocyte apoptosis. Ten days of GCs administration increases OC number (by reducing osteoclast apoptosis) and decreases OB production [59]. Loss of osteocytes disrupts the osteocyte-canalicular network resulting in a failure to detect trophic signals that normally stimulate mechanisms associated with the replacement of damaged bone. GCs induce focal alterations in the mechanical properties of trabecular bone with a reduction in the elastic modulus both at remodeling sites and around the osteocyte lacunae in the trabeculae [29]. Using Raman microscopy, it has been found that bone matrix changes in the vicinity of osteocytes lacunae are due to a reduction in the mineral to matrix ratio. This suggests that GIOP results not only from changes in trabecular mass and microarchitecture, but also to changes in the quality on the bone matrix itself. Animal models have shown that GC excess is associated with an early activation of genes associated with osteoclastogenesis and adipogenesis and a later suppression of genes associated with osteogenesis. In addition, the expression of genes expressed in osteocytes associated with bone mineralization (Dmp1 and Phex) was significantly higher at the later time points [97]. Others’ animal models in GIOP have been reported: beagles [98], ewes [99], rabbits [100], pigs [101103], and zebrafish [104] (Table 5).
Table 5

Animal models of GIOP

Animal model

Action in vivo

Mouse

↓ BMD, ↓ bone formation, ↑ bone resorption

Rat

↑ BMD or ↓ BMD

↑ BV or ↓ BV

Inhibition of bone formation and bone resorption

Rabbit

↓ BV, ↓ mineralizing surfaces, ↑ eroded surfaces, ↑ OB, and osteocytes apoptosis

Dog

Heterogeneity of bone loss

Ewe

↓ number of OC, ↑ eroded surfaces, ↓ osteoblastic surfaces, ↓ bone formation rates

Pig

↓ BMD, ↓ BV, ↓ markers of bone formation and bone resorption

Zebrafish larvae

Marked bone loss

BMD bone mineral density, OB osteoblast, OC osteoclast

Treatment of GIOP

Preventive Counter Measures and Lifestyle Recommendations

Preventive measures should be considered for all patients once the decision has been made to initiate a long-term GC therapy; they should be started at the beginning of GC therapy. Optimal management strategies to prevent bone loss should include the use of the lowest effective GC dose [105]. Good nutrition with adequate levels of dietary calcium should be recommended to all patients on GCs. Smoking and excessive alcohol intakes are both detrimental to bone health. Weight-bearing and muscle strengthening exercises are recommended.

Calcium and Vitamin D

Calcium and vitamin D supplementation is advised in all GIOP management guidelines. The benefit of calcium and vitamin D supplementation in the prevention of GIOP appears to be modest. Nevertheless, randomized clinical trials and meta-analysis have shown that treatment with calcium and vitamin D, calcitriol (1,25 dihydroxyvitamin D3), and alphacalcidol (1-α-hydroxyvitamin D3), is more effective in preventing GIOP than placebo or calcium alone with a relative preservation of BMD. The effect is more pronounced at the spine than at the hip [106108].

Bisphosphonates

Etidronate

Two large preventive trials using etidronate p.o., dosed at 400 mg, given cyclically every 3 months have shown that vertebral BMD improved significantly in the etidronate group compared to calcium alone and calcium and vitamin D groups [109, 110]. Analyses of pooled data from these trials subsequently reported a reduction in vertebral fractures [111].

Alendronate

Studies using alendronate 5 and 10 mg/day p.o. have shown a significant increase in lumbar spine and femoral neck BMD compared with placebo [112]. There were fewer new vertebral fractures in the alendronate groups than in the placebo group and markers of bone turnover decreased significantly in the alendronate groups.

Risedronate

Two 12-month randomized controlled trials have been performed with risedronate (2.5 or 5 mg/day) versus placebo in pre- and post-menopausal women and men aged 18–85, taking an average of 12 to 15 mg of prednisone daily. Significant increases in vertebral and femoral BMD have been observed in the risedronate-treated groups [113]. In both studies, there was a 70% decrease in the relative risk of new vertebral fractures in patients taking 5 mg/day of risedronate compared to placebo. No statistically significant effects on non-vertebral and hip fractures were found in GC users treated with risedronate.

Intravenous ibandronate was shown to decrease the rate of vertebral fractures in an open study on 115 patients with established GIOP. After 3 years, the frequency of new vertebral fractures was significantly lower in the ibandronate group compared to the alfacalcidol group (8.6 vs. 22.8%) [114].

Intravenous pamidronate was shown to significantly increase BMD at the lumbar spine, femoral neck, and total hip when compared to calcium alone in a randomized, placebo-controlled trial of 32 patients beginning chronic GC therapy [115].

Intravenous zoledronic acid (5 mg) is more efficient than oral 5 mg/day risedronate to increase lumbar spine BMD from baseline to 12 months in men and women, for both treatment and prevention. A single infusion of zoledronic acid 5 mg suppresses bone turnover (β-CTx, P1NP) significantly more than daily oral risedronate for up to 1 year [116, 117].

Recombinant Human Parathyroid Hormone

In a 12-month, randomized clinical trial in post-menopausal osteoporotic women who were taking GCs and hormone replacement therapy (HRT), a marked improvement of BMD at the vertebral and femoral sites was demonstrated after daily injections of human parathyroid hormone 1–34 (teriparatide) given subcutaneously for 12 months. The BMD gain was maintained during the follow-up period of 12 months off treatment. However, no difference in the fracture rate was found between both groups. In a 18-month randomized, double-blind, controlled trial [118] comparing teriparatide (20 μg s.c. once daily) with alendronate (10 mg p.o. once daily) in GCs users, the mean BMD increase at the lumbar spine was significantly larger in the teriparatide group than in the alendronate group. New vertebral fractures were less frequent in the teriparatide group than in the alendronate group and the incidence of non-vertebral fractures was similar in the two groups.

Hormone Replacement Therapy

The substitution of gonadal sex hormones is mentioned as an option for patients using GCs but there are limited data to support the use of HRT to treat osteoporosis in patients receiving prolonged therapy with GCs. In a subgroup analysis of 42 women from a study of 200 post-menopausal women with rheumatoid arthritis who were receiving low-dose GCs, HRT recipients had a significant increase in lumbar spine BMD relative to controls although femoral neck BMD was not significantly changed in either group [119]. Twelve months of treatment with testosterone injections significantly increased mean lumbar spine BMD by 5% relative to controls in 15 men with asthma receiving GCs [120].

Others Treatments

Calcitonin

Several studies have concerned the use of subcutaneous and nasal spray calcitonin in GIOP. None showed a significant decrease in fracture risk after 12–24 months of follow-up. A meta-analysis showed that calcitonin prevented bone loss at the spine and forearm after the first year of therapy, but had no effect on bone loss at the hip. Calcitonin was not statistically different from placebo at preventing fractures of the spine or hip fractures [121].

Vitamin K2 (menatetrenone) is approved in Japan for both prevention and treatment of osteoporosis. Studies have shown that vitamin K2 reduces vertebral and hip fractures and improves bone quality [122].

Denosumab

Specific studies in GIOP have not been done yet but effects of denosumab on structural damage, BMD, and bone turnover in rheumatoid arthritis are promising [123].

Studies with strontium ranelate on GIOP are underway but results have not been presented yet. Data using the selective estrogen receptor modulator raloxifene to treat or prevent GIOP are lacking.

Conclusion

GCs have outstanding therapeutic effects and are some of the most important drugs in clinical use today. Unfortunately, GC therapy is sometimes accompanied by severe and/or irreversible side effects like osteoporosis. The different molecular mechanisms of GC actions are better understood and support a certain number of starting points for the development of optimized and/or new GCs and GC receptor ligands such as selective GC receptor agonists that could improve clinical medicine by demonstrating a better benefit–risk ratio compared with conventional GCs [3, 124, 125]. Abnormalities in bone quality associated with GCs can occur even before deleterious effects on BMD are observed. For this reason, GIOP guidelines differ in the use of BMD criteria to recommend treatment for GC users (the intervention threshold of the Royal College of Physicians is a T score of −1.5 [126] and those of the American College of Rheumatology is a T score of –1 [105]). Nevertheless, every patient receiving GC therapy should have a bone assessment in order to receive calcium, vitamin D, bisphosphonates, or anabolic agents if necessary.

Acknowledgment

This study was made possible by grants from the Bioregos “Pays de la Loire” program and INSERM and was also supported by a grant from the French Society for Rheumatology (SFR).

Copyright information

© Humana Press Inc. 2009