Trabecular bones and the cortical rim of vertebral bodies are more susceptible to the effects GCs compared to the cortical component of long bones (radius, humerus) (49-52). Under GC treatment, lumbar BMD shows significantly greater bone loss compared to distal radius BMD. Bone loss is also observed in the proximal femur (particularly at Ward’s triangle, an area rich in trabecular bone) (53, 54). Although bone remodeling is initially turned on with higher bone resorption, over time, resorption parameters fall and bone becomes quiescent (19, 55). Thus, with prolonged GC administration, cortical bone becomes increasingly affected and long bones show increased fragility.

Bone biopsies of patients on GC therapy > 12 months show increased bone resorption, a decline in all aspects of bone formation and decreased trabecular volume. Histomorphometric studies on subjects with GCOP show increased osteoclasts and bone-resorbing sites. Bone loss is higher in the metaphyses compared to the diaphyses (15, 56, 57). GCOP differs from post-menopausal OP in terms of microanatomical appearance: In GCOP the number of trabeculae and their surface area are relatively preserved, and individual plates are very thin (trabecular attenuation), although still connected, whereas in post-menopausal OP, trabecular width is relatively preserved but the lamellae are perforated by resorption, with a loss of trabecular surface and continuity (58). Such changes may lead to lower mechanical strength of bone. The particular histology of GCOP may have important implications for pharmacologic intervention: the preservation of thinned trabeculae in GCOP may provide the foundation for new bone apposition.

GCs have genomic and non-genomic actions. Genomic actions result from the binding of GCs steroids to specific cytoplasmic receptors (of the nuclear receptors superfamily). The GC-GR complex can either activate or repress the expression of target genes. While activation requires binding of a dimerized receptor to GC-responsive elements (GREs) in the promoters of target genes, repression is mainly mediated by interaction between receptor monomers and transcription factors (59). Translation of GR mRNAs produces two GR isoforms, GRα, which is transcriptionally active and GRβ, which can heterodimerize with GRα, inhibiting its transcriptional activity (60). In humans, normal osteoblasts, and specific osteoblastic cell lines show GRα expression, whereas mature osteoclasts show no GRα expression. Osteoclasts, in contrast, predominatly show GRβ expressions. Osteoblasts and osteoclasts also express mineralocorticoid receptors (MRs) that bind to cortisol and form heterodimers with both GRα and GRβ (61). IL-6, in human osteoblasts, acts as an autocrine positive modulator that upregulates the number of GRs (62, 63). Cortisol, even at physiologic concentrations, modulates negatively the secretion of IL-11, a cytokine that decreases GR expression (64). Consequently, this interplay of cytokines through autocrine/paracrine loops may modulate bone sensitivity to GCs (65).

GCs increase the apoptosis of osteoblasts and mature osteocyte via activation of caspase 3 (66-68). Apoptosis may involve decreased expression of the Bcl-2 gene and increased expression of the Bax gene (69). Furthermore, reduced osteoblast differentiation may be the result of GC-induced repression of bone morphogenic protein-2 (BMP-2) and expression of core binding factor a1 (Cbfa1) (69). GCs also modify the expression of osteoblast specific genes, such as osteocalcin. Osteocalcin expression during the development of bone is tightly regulated by GCs, and multiple GREs have been identified on the human and rat osteocalcin promotert (70, 71). The osteocalcin gene also contains several activator protein-1 (AP-1) sites that apparently contribute to the basal activity of the promoter. Therefore, repression of osteocalcin promoter activity by GCs may also involve interaction between GR and components of the AP-1 complex, independently of DNA binding, as it has been postulated for the collagenase promoter (72, 73).

The Wnt signaling pathway is important for osteoblast differentiation and function, bone development and level of peak bone mass (74). Mechanical loading results in increased bone mass in animals that carry activating mutations of LRP5 (74). Interestingly, Wnt signaling may be implicated in the response to mechanical loading (74) and the observed inhibition of skeletal growth by GC may be mediated by effects that they exert on Wnt signaling (75).

GCs suppress the synthesis of type I collagen and b-1 integrin (two major components of the matrix) and increase the synthesis of collagenase 3 (or MMP-13; a metalloproteinase which cleaves collagen fibrils), inhibiting bone matrix formation by osteoblasts (76, 77).

Compared to effects of GCs on osteoblasts, the effects of GCs on osteoclasts are less known due to the inherent difficulties of study: osteoclast isolation from bone is technically difficult to perform and bone marrow cultures, haematopoietic cell lines and cells derived from giant-cell tumors (used as model systems to study osteoclast differentiation and activity) have given varying results. Recently, transgenic mouse technology has allowed the generation of two osteoclastic cell lines (78). In vitro studies on isolated osteoclasts and bone organ cultures had suggested that GCs may inhibit bone resorption (79, 80), although more recent studies indicate that GCs may, in fact, stimulate bone resorption (81-83). GC-regulated osteoclast formation and activation remain unclear. Both increased cell recruitment and activation of quiescent cells have been proposed (84). It has been shown that GCs stimulate osteoclast differentiation and their capacity to bind to the bone surface by altering the expression of N-acetylglucosamine and N-acetylgalactosamine (85). However, GCs cannot affect directly the bone-resorbing activity of mature osteoclasts, since these cells apparently do not have functional GRs (86). Higher expression of the GR gene in subjects with lower BMD may lead to higher sensitivity of their monocytes/macrophages to GCs to differentiate into osteoclasts (87). Cytokines are also implicated in these actions (see next section on regulation of bone local factors by GCs) (88).

Cytokines: Interleukin-1 (IL-1) and interleukin-6 (IL-6) induce bone resorption and inhibit bone formation. GCs partially inhibit the production of IL-1 and –6 and inhibit the bone resorbing activity of these cytokines (GC therapy could paradoxically protect osseous tissue from IL-induced bone resorption) (89-92). TGF-b (which inhibits IL-1-induced bone resorption and stimulates osteoblast activity) is decreased by GCs. (93). Lower levels of TGF-b may increase the susceptibility of bone to the resorbing effects of IL-1. IL-1 suppression also inhibits the generation of nitric oxide, which modulates osteoclast activity (94). GCs interfere with the receptor activator of the nuclear factor-κB ligand (RANKL or TRANCE)-osteoprotegerin (OPG) axis. RANKL (which is expressed at high levels in pre-osteoblast/stromal cells) induces osteoclast differentiation in the presence of colony-stimulating factor-1 (CSF-1) by binding to the receptor activator of the nuclear factor-κB (RANK; a member of the TNF family on the surface of octeoclasts) (91). OPG is also produced by osteoblasts and is found on their surface. OPG acts as a decoy receptor of RANKL: it binds RANKL and prevents it from binding its osteoclast receptor, therefore inhibiting osteoclast differentiation. GCs enhance RANKL and CSF-1 expression (65), and lower OPG expression in human osteoblasts cells in vitro (95). Serum OPG concentrations are significantly reduced in patients undergoing systemic GC therapy (96). This decrease in OPG is more marked than the GC-induced increase in RANKL, leading to an increased RANKL/OPG ratio that may mediate GC-induced bone resorption (97).

Growth factors: Insulin-like growth factors (IGFs) have an anabolic effect on bone cells that IGF-I and IGF-II receptors. IGF-I and IGF-II are weak mitogens (they increase the replication of osteoblasts), they increase type I collagen synthesis and matrix apposition rates. and decrease collagenase-3 (metalloproteinase-13) expression by osteoblasts (98, 99). Synthesis of IGF-I in osteoblasts is decreased by GCs via increased expression of the CAAT/enhancer binding protein (C/EBP) β and δ (transcription factors that bind to the IGF-I promoter and halt its transcription) (100). GCs inhibit IGF-II receptor expression in osteoblasts (while they have no effect on IGF-I receptor expression)(101, 102). Since the IGF-II receptor functions as an IGF-binding protein (IGFBP) its inhibition by GCs may result in higher levels of available growth factors although it may also lead to faster degradation of IGF-II. The activity of IGF-I and -II is regulated by at least six IGFBPs that are expressed by osteoblasts (103, 104). IGFBPs in skeletal cells are considered to be local reservoirs and modulators of IGFs. GCs decrease the expression of IGFBP-3, -4, and -5 in osteoblasts (105, 106). IGFBP-5 stimulates bone cell growth (and enhances the effects of IGF-I); its reduction in the bone microenvironment may be relevant to the inhibitory actions of GCs on bone formation and the process of GCOP (107). GCs also increase the synthesis of IGFBP-related proteins (IGFBP-rPs; a family of peptides related to IGFBPs that bind IGFs and are involved in cell growth) (108).

Bone cells express transforming growth factor-b (TGF-b) -1, -2, and -3 genes (109). TGF-b stimulates bone collagen synthesis and matrix apposition rates, modifies bone cell replication, stimulates growth and proliferation of osteoblasts but inhibits their differentiation and the expression of osteocalcin (110, 111). TGF-b1 expression in osteoblasts is not modified by GCs. GCs, instead, induce activation of the latent form of TGF-b1 by increasing the levels of bone proteases (112, 113). Two signal-transducing TGF-b receptors are expressed in osteoblasts. GCs shift the binding of TGF-b from these receptors to betaglycan (by increasing the synthesis of this proteoglycan) and oppose the effects of TGF-b osteoblastic cell replication (112).

Hepatocyte growth factor (HGF) is produced by both osteoblasts and osteoclasts. HGF is a potent stimulator of osteoblastic function and a potent suppressor of bone resorption in isolated rat osteoclasts (114). Osteoclast-produced HGF (in an autocrine fashion), may lead to changes in osteoclast shape and stimulate osteoclast migration and chemotaxis, while (in a paracrine fashion) may lead osteoblasts to enter the cell cycle, via DNA synthesis stimulation (114, 115). GCs inhibit the release of HGF in vitro, which suggests that the inhibitory effects on bone resorption of GCs may be in part mediated via regulation of osteoblast-produced HGF (116, 117).

Platelet-derived growth factor (PDGF) is a mitogen of bone cells (118). PDGF-A and PDGF–B are expressed in a limited fashion in osteoblasts, and neither the synthesis nor the binding of PDGF appear to be modified by GCs. Specific PDGF-A/B binding proteins are lacking, although SPARC (secreted protein acid rich in cysteine) and osteonectin (a protein abundant in bone matrix) bind and prevent the biologic actions of PDGF-B (119). Since GCs enhance osteonectin expression in osteoblastic cells they may also decrease the activity of PDGF-B in bone (120).

Prostanoids: Prostaglandins (PGs) are produced by bone cells and affect both bone formation and resorption. PGs (and PGE2 in particular) stimulate bone collagen and non-collagen protein synthesis (121-123). PGs inhibit directly the activity of isolated osteoclasts and increase bone resorption in organ cultures, (probably by promoting osteoclastogenesis). GC-induced inhibition of collagen synthesis in bone, down-regulation of c-fos oncogene expression and reduced osteoblast proliferation are all reversed by exogenous PGE2 in vitro, suggesting an important pathogentic role for this PG in GCOP (124-128). GCs interfere with the production of PGs in bone (especially of PGE2) via the decreased expression of cyclooxygenases (the enzymes that convert arachidonic acid into PGs) (129, 130). Osteoblasts express two cyclooxygenases: constitutive prostaglandin synthase-1 (PGHS-1) and inducible prostaglandin synthase-2 (PGHS-2). Apparently, GC-inhibited PG-production in bone is mediated through a decrease in agonist-induced PGHS-2 expression..Extraskeletal mechanisms of GCOP

Effects of GCs on calcium absorption and excretion: Although there is no consensus regarding the effect of GCs on calcium absorption they mainly appear to impair intestinal calcium absorption (131-138). GCs have no effect on the intestinal brush border membrane vesicles (139), but they decrease synthesis of calcium binding protein and deplete mitochondrial ATP (inhibiting calcium release by mitochondria) (140). Patients treated with GCs show increased renal calcium loss (ultimately leading in some patients to the development of secondary hyperparathyroidism) (141). In normal subjects receiving GCs the elevation of fasting urinary calcium proceeds the rise in immunoreactive parathyroid hormone (iPTH) (142). In patients on long-term GC therapy, hypercalciuria is most likely due to increased skeletal mobilization of calcium and decreased renal tubular reabsorption that occurs in spite of elevated PTH levels. The GC-induced decrease in bone formation lowers calcium uptake by newly formed bone and elevates the filtered load of calcium. High dietary sodium intake increases renal loss of calcium whereas sodium restriction and thiazide diuretics lower renal loss of this mineral (143).

Effects of GCs on the excretion of phosphorus: GCs acting directly on the kidney and indirectly, via induction of secondary hyperparathyroidism, lower tubular reabsorption of phosphate and lead to phosphaturia (144, 145). Furthermore, GCs increase the amiloride-sensitive Na+/H+ exchange activity in the renal proximal tubule brush border vesicles and decrease the Na+ gradient-dependent phosphate uptake; increased acid secretion and phosphaturia follow (146).

GC effects on parathyroid hormone (PTH): A direct stimulatory effect of GCs on PTH secretion may exist (144, 147, 148). More particularly, GCs induce a negative calcium balance that leads to secondary hyperparathyroidism: in patients receiving GCs iPTH is increased (this increase is abrupt if the GCs are administered i.v.). The rise in iPTH can be suppressed with exogenous calcium and vitamin D (148, 149). Chronic GC administration is accompanied by altered secretory dynamics of PTH; more particularly, it reduces its tonic secretion and increases its pulses (150). However, elevated iPTH levels can also be be suppressed by infusing calcium, suggesting that the elevation is more likely to be secondary to a negative calcium balance caused by GCs, rather than to direct stimulation of PTH secretion by these steroids (151). Responses to PTH may be increased by GCs: the rise in serum cyclic adenosine monophosphate (cAMP) stimulated by PTH infusion doubled after a three-day pretreatment with prednisone (144).

Laboratory evaluation for GCOP should include total blood cell count, markers of renal and liver function, serum electrophoresis, serum and 24-hr urine calcium, serum levels of 25-hydroxyvitamin D, alkaline phosphatase, thyroid-stimulating hormone and parathyroid hormone, estradiol in women and total and free testosterone in men (186-189).

In patients receiving GCs a dose-dependent decrease in serum osteocalcin is found; this is a good indicator of the degree of inhibition of osteoblastic activity (190, 191). Other markers of bone formation, such as total and bone specific alkaline phosphatase and procollagen type I carboxy-propeptide are also lower in under GC therapy (142, 192). In subjects on GC therapy baseline levels of osteocalcin do not always correlate with subsequent bone loss (193-195). In some, but not all, studies of patients treated with GCs, markers of bone resorption (like urinary collagen N-telopeptides [NTX]) are elevated (145, 196-198). In view of such discrepancies, the measurement of serum markers of bone formation and resorption is considered to be of little clinical utility and it is not currently advocated for routine use (185).

Changes in BMD early on during GC therapy can be detected by dual-energy X-ray absorptiometry (DEXA) and quantitative computed tomography (QCT); classic X-ray studies are useful to detect vertebral compression fractures. Both QCT and DEXA can measure cortical and trabecular bone density, however, the former is mostly used to evaluate trabecular bone density, whereas the latter is used to measure cortical and trabecular bone density (199, 200). DEXA also helps estimate the risk for fractures, and provides an objective measurement to judge the efficacy of treatment (with minimal irradiation burden) (189, 201, 202). BMD measurment techniques that focus on the vertebral body and exclude the cortical bone of posterior processes, such as lateral DEXA scanning, are apt to be more sensitive in detecting GCOP (52, 203). However, the selection of a BMD assessment method is influenced by the presence of vertebral deformities, osteophytes, or of calcifications in the aorta that may spuriously elevate spinal BMD values. If this is the case, lateral views of the vertebral bodies (particularly in the decubitus position) are considerably less precise than antero-posterior scans, and therefore less appropriate for following up changes in bone mass. When marked osteophytosis or scoliosis of the spine is seen, proximal femoral densitometry (in the femoral neck) should be chosen (53).

The finding that subjects with GCOP suffer fractures at a higher threshold of BMD than those affected by age-related or postmenopausal OP is disputed (21, 23). A T-score threshold value of – 1.5 SD is usually the cutoff for GCOP in Eurpoe (4), whereas the American College of Rheumatology (ACR) has defined the T-score cut off to – 1.0 SD to separate “normal” from “not normal” BMD (188). Furthermore, the ACR recommends BMD baseline measurements at the lumbar spine and/or hip before starting any GC treatment longer than 6 months (188). At 6 month intervals from the baseline assessment, or at 12 month intervals, if the patient is receiving therapy to prevent bone loss, follow-up measurements should be done (204). For the United States in particular, Medicare reimburses BMD evaluation for patients on chronic treatment with GC doses higher than 7.5 mg/day of prednisolone equivalent (205).

Evaluation of bone loss in GC-treated patients has been implemented with quantitative ultrasound (QU) evaluations at the heel and hand phalanges (206, 207). Currently the relevant data available are very limited to assess whether QU is be suited for routine clinical practice.

As soon as GCs are administered prevention of GCOP should start; bone loss is more rapid in the first months of therapy. The minimal effective GC dose should be used with the option of alternate-day therapy to preserve the normal response of the hypothalamo-pituitary-adrenal axis. GCs with shorter half-life should be preferred and topical or inhaled preparations whenever possible.

The concept of “safe dose” for the treatment with oral GCs is controversial (19). More particularly, prednisone given at low doses (5-9 mg/d) may affect BMD whereas lower doses (1-4 mg/d) were reported to have very little or no skeletal effect (209). However, a single oral dose of 2.5 mg of prednisone has an almost immediate negative effect on osteocalcin secretion (210). Alternate-day GC administration may prevent growth retardation in children but not bone loss (40, 211).

The effects of inhaled GCs on BMD are not completely clear. The newest inhaled GCs (such as budesonide), seem to have less adverse effects on the bone, as indicated by bone markers (212, 213). Dosing of the inhaled GC is important: beclomethasone dipropionate or budesonide given at low doses for more then one year did not affect spine BMD in asthmatic subjects (213). However, patients treated with high doses of inhaled budesonide or beclomethasone (1.5 mg/day, for at least 12 months) and without prior oral GC treatment for more than 1 month, had a significant decrease in bone mineral density (BMD) and bone formation markers, with no changes in bone resorption markers (214). In a recent study, inhaled GCs in adults with chronic lung disease were not associated with increased fracture risk (and more in detail no dose-response curve was verified) (215). Moreover, in children treated with beclomethasone for bronchial asthma, analysis after adjustment for the severity of the underlying disease did not show any association between inhaled GCs and fracture risk (216). Thus, in children, other factors, such as excess body weight, low muscle mass and limited exercise capacity may predispose to low BMD (217).

Another factor that should be noted is the change in lifestyle for the prevention of GCOP. Alcohol and sodium intake should be reduced, smoking should be stopped and a regular exercise program should be followed (25). Subjects on GCs may benefit if they are protected from falls (185, 218).

Therapy for GCOP aims to prevent and minimize bone loss, to increase BMD and, at least partially, to reverse the effects of GC excess. Therapy should be continued for as long as GC therapy is pursued.

Calcium and Vitamin D supplementation: Patients on GCs should receive supplementation with 1,500 mg/d of calcium and 800 IU/d of vitamin D (1 μg/day of α-calcidiol or 0.5 of μg/day calcitriol) to oppose the negative calcium balance (188). A two-year randomized clinical trial demonstrated the efficacy of combined calcium and vitamin D supplementation in preventing bone loss in patients with rheumatoid arthritis treated with low doses of GCs (219). However, these encouraging findings were not replicated in a three-year follow-up study, where the same combination did not show any benefit (220). From randomized clinical trials and meta-analyses it was shown that active metabolites of vitamin D (α-calcidiol and calcitriol) are more effective than vitamin D in maintaining bone density during medium-to-high dose GC treatment (221-223). Treatment with active forms of vitamin D entails a risk of hypercalciuria and hypercalcemia, consequently periodic assessment of serum calcium and creatinine levels at the beginning of the therapy, after 2-4 weeks, and thereafter every 2-3 months is advised (224, 225).

Thiazide diuretics lower urinary calcium excretion. Chronic treatment with thiazides decreased the incidence of hip fracture in elderly patients, and increased BMD in the general population (226-228). This evidence suggests that, together with sodium restriction, they may be useful in opposing calcium loss and secondary hyperparathyroidism caused by chronic GC therapy. However, there are currently no studies showing long-term effect of thiazide diuretics on BMD in patients treated with GCs.

Antiresorptive therapy: There are several antiresorptive agents available for the prevention and treatment of GCOP. Bisphosphonates are the most widely used.

Bisphosphonates decrease the resorptive activity of osteoclasts, increase osteoclast apoptosis and decrease osteoblast and osteocyte apoptosis (229). Their efficacy in preventing and treating GCOP has been clearly shown in large randomized controlled clinical trials (230). Treatment with alendronate for 18 months or two years increased total body BMD, and significantly decreased risk of vertebral fractures in patients taking GC (231, 232). Similarly, a one-year study with risedronate in patients taking prednisone (7.5 mg/day for at least 6 months) showed an increase in lumbar spine and femoral neck BMD and a 70% decrease in the relative risk of vertebral fractures (233). Cyclic etidronate (400 mg/day for 14 days every three months for one year) was proven to both prevent bone loss in patients taking GCs for rheumatoid arthritis and polymyalgia rheumatica, and reverse OP in patients on chronic treatment with prednisone (234, 235). Both oral (150 mg/day) and intermittent i.v. (30 mg every three months for one year) pamidronate disodium increased BMD at the spine and the hip in patients starting long-term GC therapy (236, 237). Clodronate increased BMD in asthmatic patients treated with GCs (238). Zoledronic acid (a long-acting potent bisphosphonate) given intravenously (4-10 mg once or twice a year) has excellent anti-OP results (239-244).

Currently, alendronate (5 and 10 mg/day or 70 mg/week) and risedronate (5 mg/day or 35 mg/week) are recommended in the United States to treat men and postmenopausal women starting long-term GC treatment (≥ 5 mg/day) (188). Ibandronate sodium, is a bisphosphonate administered once monthly (150 mg). It increases BMD and lowers fracture risk similarly to alendronate given once weekly (245). Using it for GCOP seems logical, although published reports on the actions of ibandronate specifically in GCOP are not available.

Calcitonin, in nasal or subcutaneous formulations, reduced bone loss in patients treated with GCs for asthma or sarcoidosis and decreased OP-related pain (246, 247). Nevertheless, there is no evidence that this antiresorptive agent could diminish the risk of osteoporotic fractures. Treatment with nasal calcitonin (200 IU/day) may be considered whenever biphosphonates are contraindicated or not well tolerated, or in patients with fractures-associated pain, because of its analgesic effect (248).

Anabolic therapy: Anabolic medications enhance bone formation, therefore antagonizing the suppressive effect of GCs on osteoblast activities. However, much of the information on the use of these compounds to prevent or treat GCOP comes from small studies.

Sodium fluoride, in combination with either calcium and vitamin D, or cyclic etidronate, improved lumbar spine BMD and trabecular bone volume in GC-treated patients. However, no reduction in the incidence of fractures was observed. Moreover, fluoride induced bone loss at the femoral neck (249, 250). Since most of the evidence indicates that sodium fluoride does not provide architecturally competent bone, its use is currently not recommended for GCOP (188).

Anabolic steroids have also been tested in GCOP. Cyclic nandrolone decanoate (50 mg i.m. every three weeks for six months) increased the forearm bone density in GC treated women, 10% of which developed virilizing side effects (251). Similarly, cyclic medroxyprogesterone acetate (200 mg i.m. every 6 weeks for one year) augmented lumbar spine BMD in treated men (252). Currently, there is no recommendation for the use of anabolic steroids for GCOP.

Recombinant PTH administration (400 IU of PTH 1-34; teriparatide) to postmenopausal women on prolonged estrogen replacement, who had developed OP after chronic GC therapy, resulted in increased lumbar spine bone mass, assessed by both DEXA and QCT, which was maintained after discontinuation of the teriparatide treatment (253, 254). Teriparatide should be a first-choice therapy (20 microg/day sc) for patients with GCOP and fractures (255, 256). The combination of teriparatide and bisphosphonates is not advocated; the latter may lower the effectiveness of the former (257). Nevertheless, bisphosphonates given after stopping teriparatide therapy may help to maintain bone formed teriparatide (258).

Gonadal hormone replacement: Sex hormone treatment should be considered whenever a patient with GC excess develops hypogonadism (230). A retrospective study in postmenopausal women taking GCs found an increased BMD in those who were taking estrogens, compared to increasing bone loss in those who were not (259). Moreover, in a randomized controlled clinical trial of postmenopausal women taking GCs for rheumathoid arthritis, a significant increase in lumbar spine BMD was observed in those receiving hormone therapy (HT) compared to those receiving placebo (260). This evidence suggests the potential benefit of HT in hypoestrogenic women treated with GCs. However, recently a large randomized clinical trial in postmenopausal women treated with a combination of estrogen and progestin planned to last 8.5 years was interrupted after 5 years, because the overall risks exceeded the benefits of the treatment (261). Nevertheless, the ACR recommends oral contraceptives (unless contraindicated) in premenopausal women on GCs who develop oligo-amenorrhea (188). Similarly to women, adult men with GC excess who develop hypogonadism could benefit from testosterone replacement. In GC-treated asthmatic men with testosterone deficiency, i.m. testosterone injections increased lumbar spine BMD, but not hip BMD (262). There are no data on the potential benefit of testosterone therapy in GC- treated eugonadal men. However, since most studies have shown an increase in prostate size and prostate-specific antigen levels in older men on testosterone supplementation/therapy (263-266), testosterone administration should be monitored with yearly rectal examinations and prostate-specific antigen measurements.

In addition to different combinations of the treatments so far discussed, selective estrogen receptor modulators (SERMs) and selective GR modulators (SGRMs) may be part of the pharmaceutic armamentarium against GCOP.

SERMs, such as tamoxifen and raloxifen have positive effects on the bone. Tamoxifen reduces in vitro some of the deleterious effects of GC on the bone (267). Raloxifen, which is currently approved by the United States’ Food and Drug Administration (FDA) for the prevention and treatment of postmenopausal OP, might be a safer alternative to HT in the treatment of GCOP that develops in postmenopausal women, given its favorable effects on serum lipids, together with the lack of growth stimulation on endometrial and breast tissues (268, 269). SGRMs are selective ligands of the GR which maintain the transrepressive properties of GCs (usually associated with their beneficial anti-inflammatory effect) while they do not have their transactivating properties (usually associated with metabolic negative effects, including perhaps those on the bone). Some of these molecules may represent an alternative to traditional GCs in the chronic treatment of inflammatory disorders (270).

Initial experience with strontium ranelate shows it to be roughly as effective as bisphosphonates in treating osteoporosis. It has yet to be evaluated for GCOP.

Other newer agents that are tentatively evaluated for the treatment of osteoporosis either inhibit osteoclast resorption or stimulate osteoblast bone forming activity. These include recombinant osteoprotegrin, antibodies against RANKL, inhibitors of osteoclast enzymes, integrin antagonists and agonists to LRP5 (255). Glucocorticoid discontinuation and reversibility of GCOP

There is no consensus on the reversibility of GCOP. Bone mineral density increases after curative surgery for Cushing’s disease or interruption of exogenous GC treatment (271-273). A prospective study in patients with rheumatoid arthritis showed partial bone regain after discontinuation of low-dose GC therapy that was given for five months (15). In patients with sarcoidosis younger than 45 years full recovery of bone mass was reported two years after cessation of therapy (274). However, it is unlikely that the large (10% or more) bone mass that is lost during high-dose GC therapy can be completely regained, with full recovery of the mechanical properties of the bone. The likelihood of bone regain may be negatively correlated with the duration of treatment as well as unknown host-related factors. Most complications of osteoporotic fractures, such as vertebral deformities and chronic back pain, are permanent.