Management Of Glucocorticoid Induced Osteoporosis

StateUniversityofMedicine andPharmacy

"Nicolae Testemițanu"

Faculty of General Medicine II

Department of rheumatology and nephrology

Management of glucocorticoid- induced osteoporosis

(literature review and clinical study)

Diploma Thesis

Student: Fadi Fodi

Group: 1551

Academic adviser: Cepoi-Bulgac Daniela

MD, PhD, Associated Professor

Chișinău, 2016

Index

Introduction

Osteoporosis from all causes is a  main health threat, affecting approximately 20 to 25 million in the United States (Cunnane and Lane 2000) An additional 18 million people havelow bone mass, that put them at risk for osteoporosis. (NIH Panel, 2001) Although it wasonce thought to be a disease widly affect elderly women, osteoporosis is no longerconsidered age or sex dependent. (NIH Panel, 2001)Osteoporosis is a main complication of GCs treatment, revolving in at least50% of patients who want long-term steroid therapy and carrying significant physical as well asfinancial and psychosocial result for affected people and their families andcommunities. (Lukert and Raisz 1990; Saag et al. 1998, 1999; NIH Consensus DevelopmentPanel, 2001) Even more alarming than the impact of the disease itself is the toll osteoporosistakes in the form of related fractures. More than 1.5 million osteoporosis-related fractures occureach year in the (Lukert and Raisz 1990), with an estimated treatment cost of 10 to15 billion dollars in direct financial expenditures (NIH Panel, 2001). This does not include the indirect

costs of lost wages and lost productivity of the patient and caregiver, and thus these figuresrepresent a significant underestimate of the true impact of osteoporosis in this country.Despite the prevalence of GIO , its treatmentremains relatively neglected, and many patients receiving long-term GCs therapyreceive no prophylaxis against bone loss. (Brand et al. 1999; Saag et al. 1999; Soucy et al. 2000;Valentine and Sninsky 1999; Walsh et al. 1996).

The aim of this review is to examine the mechanism of action and severity of bone loss in GIO, discuss additional risk factors forosteoporosis in diseases treated with GCs, and sum the findings in recentstudies of bisphosphonate treatment for osteoporosis, focusing primarily on studies ofrisedronate, which is  presently the only bisphosphonate approved for the prevention of GIO.

Definition

Osteoporosis is a systemic skeletal disease characterised by decrease in bone mass and micro-architectural deterioration of bone tissue with a subsequent increase in bone fragility and susceptibility to fracture [1].(Figure1)

(Figure1): osteoporosis of bone .

Types of osteoporosis

Primary

Juvenile idiopathic

Idiopathic of middle age

Involution – aging
Type I (postmenopausal)
Type II (senile)

II. Secondary causes

the loss of bone mass is caused by specific lifestyle behaviors, diseases, or medications.(Figure2)

(Figure2) : secondary causes of osteoporosis.

(Figure3) : secondary causes of osteoporosis.

Basic biology of bone remodeling

Bone remodeling is carried out by a functional and anatomic structure known as the basic multicellular unit (BMU) and needs the arrenged action of 4 main types of bone cells: bone-lining cells, osteocytes, osteoclasts, and osteoblasts (Figure 4) [3, 4]. In a quiet state, the bone exterior is covered by a monolayer of bone-lining cells, which belong to the osteoblast lineage [5, 6]. Osteocytes are the most  numerous bone cells; they also differentiate from osteoblasts and are firmed within the bone during skeletal development or during past cycles of bone remodeling [7]. Osteocytes may be as the primary mechanosensing cells, and therefore they maybe play a pivotal role in the initiation of bone remodeling [8]. Osteoclasts, the sole bone resorbing cells, are multinucleated giant cells that differentiate from mononuclear cells of the monocyte/macrophage lineage upon stimulation by two essential factors: the monocyte/macrophage colony–stimulating factor (M-CSF) and the receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) [9, 10]. Osteoclast differentiation involves several key steps: Hematopoietic stem cells give rise to colony-forming unit granulocytes/macrophages, which further differentiate into cells of the monocyte/macrophage lineage in the bone marrow. Mononuclear cells of the monocyte/macrophage lineage in the bone marrow or in the circulation are considered to be osteoclast precursors, which are attracted to possible resorption sites and then attach to the bone matrix to differentiate into osteoclasts in response to M-CSF and RANKL [10, 11]. Osteoblasts, the boneforming cells, are come from mesenchymal stem cells (MSCs) through a multistep differentiation pathway. MSCs give rise to osteoprogenitors, which differentiate into preosteoblasts and then mature osteoblasts [12]. Emerging evidence indicates that MSCs and osteoprogenitors not only reside in the bone marrow but also are present in the circulation [13–15].

(Figure 4)Bone remodeling .

The remodeling process involves 4 main distinct but overlapping phases:

Phase 1: initiation/activation of bone remodeling at a specific site.

Phase 2: bone resorption and concordant recruitment of MSCs and osteoprogenitors.

Phase 3: osteoblast differentiation and function (osteoid synthesis).

Phase 4: mineralization of osteoid and completion of bone remodeling (Figure 4) [16, 17].

It has been suggested that when osteocytes either sense bone deformation caused by mechanical loading or detect microdamage in old bone, they transmit signals of an unknown nature to recruit osteoclast precursors to the specific bone site (Figure 4) [18]. Emerging evidence aid the concept that bone remodeling happens within a narrow system termed the bone-remodeling compartment , which is hardly vascular and characterized by the exist of a canopy formed by bone-lining cells [5, 6, 19]. So, osteoclast precursors may be induct either from the bone marrow, by passing the bone-lining cell monolayer, or from capillaries that enter into the BRC. Osteoclast precursors then attach to the bone matrix to differentiate into osteoclasts in response to incrase concentrations of M-CSF and RANKL within the BRC. With the formation of osteoclasts, the remodeling process income to 2 Phases , in which bone resorption represents the main event, but the recruitment of MSCs and/or osteoprogenitors into the BRC is also initiated Identically, MSCs and osteoprogenitors can be recruited either directly from the bone marrow or from capillaries that enter into the BRC. Osteoclast formation and bone resorption keep going , while recruited MSCs and osteoprogenitors differentiate into preosteoblasts and then osteoblasts throughout Phase 2. The remodeling process 3 as osteoblast function (osteoid synthesis) star to overtake bone resorptionas the main event. Phase 3 continues for some time to let the BRC to pit more bone by sap the bone surface and exchanging it with osteoid produced by osteoblasts. Osteoblast formation and function continue even after stoping of bone resorption to maintane a balance between bone removal and bone formation. Phase 4 involves the mineralization of osteoid and chop the bone-remodeling cycle (Figure 4).

The adult skeleton has approximately 1–2 million active BMUs at any given time , they are spatially and temporally detached from one another and function in an asynchronous fashion within the cortical bone and on the surfaces of the trabeculae and cortex [16] . (Figure 4) describe the key steps of a BMU remodeling bone on the surface of trabecular bone (semiosteonal remodeling); similar BMUs pit and replace tunnels in cortical bone (osteonal remodeling). Importantly, normal bone remodeling count on the tight coupling of bone formation to bone resorption to enclose no net change in bone mass or quality after each remodeling cycle. Previously, investigators conferms that 2 mechanisms control the coupling: First, a number of local and systemic factors arrange the formation and function of both osteoblasts and osteoclasts, which led to concomitant changes in bone resorption and bone formation [20, 21]. Second, growth factors such as transforming growth factor β (TGF-β), released from the bone matrix over the resorption process, share in regulating osteoblast differentiation and function [22, 23], thereby coupling bone formation to bone resorption. Interestingly, packed evidence suggests that osteoclasts play a role in the coupling of bone formation to bone resorption by making factors that stimulate osteoblast differentiation and function [24–26]. Finally, the BRC may also serve as a physical mechanism for coupling bone formation to bone resorption by attach the two biological processes in a closed compartment [19].

Understanding the basic biology of bone remodeling is hard for explanation of the molecular and cellular mechanisms following the pathogenesis of disorders of bone remodeling. The updated bone-remodeling model described in propose that the bone-remodeling process may be derailed at different levels, that let to various metabolic bone diseases. Postmenopausal osteoporosis may reflect a high primarily in the frequency of activation of BMUs, and other bone disorders may involve the effects of many systemic and local factors on the differentiation, function, and life span of bone cells. In particular, the concept of the BRC shore the notion that systemic and local factors may alter the bone-remodeling process by affecting the induction of bone cells into the BRC or by disrupting the structural safety of the BRC [27]. Moreover, the deregulation of secretion of osteoclast derived factors may share in pathogenesis of bone disorders.

Pathogenesis of fractures in GIO

Fractures may be in many as 30–50% of patients receiving chronic GCs therapy [106]. Theyoccur more in postmenopausal women and menat sites enriched in cancellous bone, such as the vertebrae and femoral neck [107Likes with vertebral fracturesoccurring in post-menopausal osteoporosis, vertebral fracturesassociated with GCs therapy often areasymptomatic [106]. When confederated by X-ray-based morphometric measurements of vertebral bodies, 37% of postmenopausal women on chronic > 6 months oralglucocorticoid therapy sustain one or more vertebralfractures [63]. Vertebral fractures can be early after exposureto GCs, at a time when BMD declines rapidly[108]. The initial rapid loss of bone predisposes to fracture ,even in individuals whose T-scores are only in theosteopenic range.Although fractures can occur early in the path of GCs therapy, their range is also related to thedose and period of GCs. Doses as lowas 2.5 to 7.5 mg of prednisolone equivalents per day can beassociated with a 2.5-fold increase in vertebral fractures,but the risk is greater at higher doses for prolonged duration [109]. Following the exposure to prednisoneequivalents of 10 mg daily for longer than 90 days, the riskof fractures of the hip and spine is increased by 7- and 17-m fold, respectively [109]. The risk of fracture decrase after stop of GCs therapy .The cause for the individual heterogeneity in theresponse to GCs is not known, but differentialresponses may be associated with polymorphisms of the GC receptor gene.

gc receptor polymorphismsare related with differences in BMD andbody composition [110]. Indeed, body composition andrisk of fracture during GCs treatment seem to high related [111]. Another explanation for individualvariability in the response of patients exposed to GCs related to peripheral enzymes that interconvertactive and inactive GCs molecules. 11β-hydroxysteroiddehydrogenases regulate the interconversion betweencortisone and hormonally active cortisol, and play arole in the regulation of GCs activity [112]. Two 11β-hydroxysteroid dehydrogenase enzymes have been described: 11β-hydroxysteroid dehydrogenase type-1 is primarily a GCs 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 mostly expressed in GCs target tissues, including bone, and its activity and the potential to generate cortisol from cortisone in human osteoblasts is increased by GCs [113].

There seems to be an converse relationship between 11β- hydroxysteriod dehydrogenase type I activity and osteoblastdifferentiation. An increase of 11β-hydroxysteriod dehydrogenase type I activity happens with aging, possibly

Providing an explanation for the reinforce sensitivity of the elderly to the effects of GCs on the skeleton [113]. A serious point that is often decrase in discussions about GIO is that many disorders for which the

GCs are prescribed are themselves causes of osteoporosis. One has to take into account, therefore, theunderlying disease itself along with the use of GCs when considering the management of GIO. IBD , rheumatoid arthritis and COPD , for example, all are related with bone loss, independent of GCs treatment [114]. 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 . However, there are other factors that play a role in the bone loss. In IBD, bone loss due to malabsorption of vitamin D, calcium and other nutrients. In COPD, acidosis, hypoxia, reduced physical activity, and smoking may all lead to bone loss, independent of the use of GCs [115].

A direct relationship between BMD and fracture risk in GIO has not been confirmed [116]. It is likely to bedifferent from that confirmed in postmenopausal osteoporosis because fractures in GIO occur at higher body mass index [117]

(Figure8). This point has to be considered when making treatment decisions in GIO. The (Royal College) of Physiciansrecommends a vertebral T-score of −1.5 as the intervention threshold. The American College of Rheumatology advise a more stringent therapeutic intervention at a T-score of ≤ −1. These scores are higherthan the treatment threshold T-Scores of −2.0 to −2.5, often used in the management for post-menopausalosteoporosis [118]. The causes for the altered relationship between BMD and risk of fracture are complex [119]. In addition to the rapid decrase in BMD that be after GCs exposure (the higher bone loss, thegreater the risk), other factors affect bone strength and fracture risk in GIO. These cotaine the underlying diseasefor which patients receive GCs, and multiple cellular prosses that lead to structural changes in bone [120].

In GIO, the negative effects of GCs on osteoblasts and osteocytes affect adversely the architecture ofcancellous bone. However, these changes often are not translated into a low in BMD. decrasing in trabecular number, thickness and connectivity cannot be determined by currently available non-invasive imaging modalities.

Newer technologies, likes high resolution peripheral quantitative computed tomography or micro magnetic resonance imaging may be benefic in identifying individual fracture risk of patients on GCs [121].

(Figure8): Relationship betweenbone mineral density (BMD)at lumbar spine and femoralneck and incidence of radio-logical spinal deformities in postmenopausal women with glucocorticoid-induced osteoporosis .

Although biochemical markers of bone turnover can be useful measures of bone remodeling activity and canpredict fracture risk, their value in GIO has not been established and their levels vary with the level of thedisease [122]. After the initial exposure to GCs , there is an increase in biochemical markers of boneresorption, which is followed by an inhibition of markers of bone formation and bone resorption [122].In addition to the direct effects of GCs on bone cells, the catabolic effects of GCs onmuscle may contribute to fracture risk since these steroids lead to muscular weakness, which can arise the incidence of falls. GCS induced myopathy may occur after early exposure to GCs [123]. Chronic CGS induced myopathy is generally manifested by weakness particularly of the pelvic girdle musculature and may influnce up to 60% of patients treated with GCs . The myopathy involves muscle loss due to GCs induced proteolysis of myofibrils [124]. This is mediated by activation of lysosomal andubiquitin-proteasome enzymes. New studies have demonstrated that GCs induce myostatin, a negativeregulator of muscle mass. Cancel of the myostatin gene block GCs induced myofibril proteolysis and muscle loss in murine models [124]. This would propose that myostatin plays a role in the mechanism of muscularatrophy in GIO.

WAYS TO THE DIAGNOSIS AND OF OSTEOPOROSIS :

The diagnosis of osteoporosis is done by measurement of BMD or by the appearance of adulthood hip or vertebral fracture in the absence of main trauma (likes a motor vehicle accident or multiple story fall)[28].

Laboratory investigations is indicated to eliminate secondary causes of osteoporosis .(Figure 5)

(Figure 5) Laboratory testingto exclude secondary causes of osteoporosis .

Bone Mineral Density Measurement and Classification

DXA measurement of the hip and spine is the technology used to confirm a diagnosis of osteoporosis, predict future fracture risk and monitor patients. Areal BMD is expressed in full terms of grams of mineral per square centimeter scanned (g/cm2) and as a relationship to two norms: compared to the BMD of a sex , age and ethnicity-matched reference population Z-score , or compared to a young-adult reference population of the same gender T-score(Figure 5).

The difference between the patient’s BMD and the mean BMD of the reference population, divided by the standard deviation (SD) of the reference population, is used to calculate T-scores and Z-scores. high bone mass is done in early adulthood, followed by a decrase in BMD. The rate of bone loss fast in women at menopause and keep to progress at a slower pace in older postmenopausal women (see Figure 3) and in older men. An individual’s BMD is approach as the standard deviation uper or lower the mean BMD of the reference population, as outlined in Table 5. The BMD diagnosis of normal, low bone mass (osteopenia), osteoporosis and severe or confirmed osteoporosis is based on the WHO diagnostic classification (Figure6).[29]

(Figure 5). Z- and T-scores in Women

(Figure6): Defining Osteoporosis by BMD

by appropriately trained technologists on properly maintained instruments. DXA scans are related to exposure to trivial amounts of radiation.

In postmenopausal women and men age 50 years and older, the WHO diagnostic T-score criteria (normal, low bone mass and osteoporosis) are done by BMD measurement by central DXA at the lumbar spine and femoral neck.[29] BMD measured by DXA at the one-third 33% radius site can be used for diagnosing osteoporosis when the hip and lumbar spine can’t be measured or are unusable or uninterpretable.[10] In premenopausal women, men less than 50 years of age and children, the WHO BMD diagnostic classification should not be used . In these groups, the diagnosis of osteoporosis should not be done on the basis of densitometric criteria alone. The International Society for Clinical Densitometry (ISCD) recommends that instead of T-scores, ethnic or race adjusted Z-scores should be used, with Z-scores of -2.0 or lower defined as either “low bone mineral density for chronological age” or “below the predicted range for age” and those above -2.0 being “within the expected range for age.” [29]

Who Should be investigated ?

The rule to perform bone density assessment should be based on an personal’s fracture risk profile and skeletal health assessment. Use any procedure to measure bone density is not indicated unless the results will affect the patient’s treatment . The America , Preventive Services Task Force recommends testing of all women age 65 and older and younger women whose fracture risk is similar to or greater than that of a 65-year-old white woman who has no additional risk factors[30].

(Figure 7) borders of indications for BMD testing. BMD measurement is not recommended in children or adolescents and is not routinely indicated in healthy young men or premenopausal women unless there is an important fracture history or there are specific risk factors for bone loss.

(Figure 7): Indications for BMD Testing :

Vertebral Imaging

A vertebral fracture is coordinated with a diagnosis of osteoporosis, even in the lack of a bone density diagnosis, and is an indication for pharmacologic treatment with osteoporosis medication to decrase subsequent fracture risk.[31] Most vertebral fractures are asymptomatic when they first happens and often are undiagnosed for many years. Proactive vertebral imaging is the only path to diagnose these fractures. The result of a previously unrecognized vertebral fracture may change the diagnostic classification, alter future fracture risk calculations and affect treatment decisions.[32]

Independent of BMD, age and other clinical risk factors, radiographically confirmed vertebral fractures even if completely asymptomatic are a sign of impaired bone strength and quality , and a strong predictor of new vertebral and other fractures. The presence of a one vertebral fracture increases the risk of subsequent fractures 5-fold and the risk of hip and other fractures 2- to 3- fold.[33] Vertebral imaging can be done with using a lateral thoracic and lumbar spine x-ray or lateral vertebral fracture assessment (VFA), available on most modern DXA machines.

VFA can be conveniently performed at the time of BMD assessment, while conventional x-ray may require referral to a standard x-ray facility.

Indications for Vertebral Imaging

Because vertebral fractures are so common in older individuals and most produce no acute symptoms, vertebral imaging tests are recommended for the individuals defined in Table 1. Once a first vertebral imaging is done, it only needs to be repeated if prospective height loss is documented or new back pain or postural change occurs. [34] A follow up vertebral imaging test is also bespoke in patients who are being believed for a medication holiday, since stopping medication would not be recommended in patients who have recent vertebral fractures.

Table 1: Indications for Vertebral Imaging

^ Current height compared to peak height during young adulthood

^^ Cumulative height loss measured during interval medical assessment

^^^ If bone density testing is not available, vertebral imaging may be considered based on age alone

Biochemical Markers of Bone Turnover

Bone remodeling (or turnover) occurs throughout life to fix fatigue damage and microfractures in bone and to keep mineral homeostasis. Biochemical markers of bone remodeling (e.g., resorption markers-serum C-telopeptide (CTX) and urinary N-telopeptide (NTX) and formation markers-serum bone specific alkaline phosphatase (BSAP), osteocalcin (OC) and aminoterminal propeptide of type I procollagen (PINP)) are best collected in the morning while patients are fasting.

Biochemical markers of bone turnover may:[35]

• Predict risk of fracture independently of bone density in untreated patients.

• Predict fastly of bone loss in untreated patients.

• Predict extent of fracture risk reduction when repeated after (3-6 months)of treatment with FDA-approved therapies.

• Predict magnitude of BMD increases with FDA-approved therapies.

• Help determine adequacy of patient compliance and persistence with osteoporosis therapy.

• Help determine duration of (drug holiday) and when and if medication should be restarted (Data are quite limited to shore this use, but studies are underway).

Additional Bone Densitometry Technologies

The following bone mass measurement technologies included in Table 2 are capable of tip both site-specific and overall fracture risk. When performed according to accepted standards, these densitometric techniques are accurate and highly reproducible.[10] However, (T-scores) from these technologies can’t be used according to the WHO diagnostic classification because they are’t equivalent to (T-scores) derived from DXA.

Table 2: Additional Bone Densitometry Technologies

GLUCOCORTICOID-INDUCED OSTEOPOROSIS

Synthetic GCs are used in a wide several of disorders, including pulmonary, gastrointestinal diseases , autoimmune, as well as in patients with malignancies and patients following organ transplantation. Although the indications for GCs in these several 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 GCs is the skeleton, and glucocorticoid-induced osteoporosis is the most common form of secondary type of osteoporosis [64]. Despite the fact that GCs can cause fractures and bone loss , many patients receiving or initiating long-term GCs therapy are not evaluated for their skeletal health.

Moreover , patients often do not take specific preventive or therapeutic agents when indicated [64]. New knowledge of the pathophysiological mechanisms underlying glucocorticoid-induced osteoporosis has been accompanied by the availability of effective strategies to prevent and treat glucocorticoid-induced osteoporosis.

Fig.Diagram showing the direct and indirect effects of glucocorticoids on bone leading to GIO and fractures.

Direct effects of glucocorticoids on bone cells :

Osteoblasts

GCs decrease the function and number of osteoblasts. These effects lead to a inhibition of bone formation, a central feature in the pathogenesis of GIO. GCs decrease the replication of cells of the osteoblastic lineage, lowing the pool of cells that may differentiate into mature osteoblasts [65]. moreover, GCs impair osteoblastic differentiation and maturation [66]. Under specific experimental conditions, on other side , GCs have been reported to favor osteoblastic differentiation [8]. In murine models, basal levels of GCs seem to be required for cortical bone acquisition and osteoblast differentiation [67]. However, the effects of GCs 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 after GCs exposure [66]. In the presence of GCs, bone marrow stromal cells, the precursors of osteoblasts, do not differentiate or are directed, instead of , toward cells of the adipocytic lineage [68]. Mechanisms involved in this redirection of stromal cells include induction of nuclear factors of the CCAAT activators binding protein family and the induction of peroxisome proliferator-activated receptor γ 2 (PPARγ 2), both of which play main roles in adipogenesis [69]. According to these observations, thiazolidinediones, which are known to activate PPARγ 2, stop osteoblastic cell differentiation in murine models. Recent observations in human subjects indicate that diabetic patients receiving thiazolidinediones have a big incidence of fractures [70]. An additional mechanism by which GCs inhibit osteoblast cell differentiation is by opposing Wnt/ β-catenin signaling [71]. 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 [72]. In this pathway, when Wnt is absent, β-catenin is phosphorylated by glycogen-synthase kinase-3β (GSK-3β), and then low by ubiquitination. When Wnt is present, it binds to specific receptors, called frizzled, and to coreceptors, low density lipoprotein receptor regard proteins (LRP)-5 and -6, leading to inhibition of GSK-3β activity. When GSK-3β is inactive, stabilized β-catenin translocates to the nucleus, where it related with transcription factors to regulate gene expression [73]. Canceling of either Wnt or β-catenin lead to 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. GCs induce Dickkopf expression and maintain GSK 3-β in an active state, leading ultimately to the inhibition of β-catenin [74]. moreover to inhibiting the differentiation of osteoblasts, glucocorticoids inhibit the function of the differentiated

GCs OSTEOCLASTS BONE OSTEOCYTES OSTEOBLASTS ⇓ Differentiation ⇓ Function ⇑ Apoptosis ⇓ Function ⇑ Apoptosis ⇑ Genesis ⇓ Apoptosis ⇓ bone formation ⇑ bone resorption ⇓ Bone Quality ⇓ Bone Mass Muscle Increased risk of fracture Myopathy ⇑ risk of falls RANKL CSF Proteolysis of myofibrils Neuroendocrine system ⇓ GH/IGF-I ⇓ sex steroids Muscle weakness Ca Metabolism ⇓ intestinal absorption ⇑ Renal excretion Negative calcium balance ⇓ Fibrils Fig. Diagram showing the direct and indirect effects of GCs on bone leading to GIO and fractures 1320 Osteoporos Int (2007) 18:1319–1328 mature cells. GCs stop osteoblast-driven synthesis of type I collagen, the main component of the bone extracellular matrix, with a consequent lowing in bone matrix available for mineralization . The lowing in type I collagen synthesis occurs by transcriptional and post-transcriptional mechanisms [75]. GCs have pro-apoptotic effects on osteoblasts and osteocytes due to activation of caspase 3, common downstream effectors of various apoptotic signaling pathways [76]. 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 effectors of multiple apoptotic signaling pathways [76]. The inhibitory effects of GCs 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 fix of bone microdamage [77]. Loss of osteocytes damge the osteocyte-canalicular network lead to a failure to detect signals that normally stimulate processes associated with the replacement of damaged bone [78]. damge of the osteocyte-canalicular network can damge fluid flow within the network adversely affecting the material properties of the surrounding bone, independent of changes in bone remodeling or architecture [78]. GCs affect the function of osteocytes, by modifying the elastic modulus surrounding osteocytic lacunae [79]. GCs induce the apoptosis of osteocytes [80]. As a result, the normal maintenance of bone through this mechanism is impaired and the biomechanical properties of bone are compromised [81].

Osteoclasts

In human subjects, GIO occurs in two phases: a fast, early phase in which bone mineral density (BMD) is decrease, presumably due to excessive bone resorption , and a slower, progressive phase in which BMD decrase due to impairedbone formation [81]. Osteoclasts are members of themonocyte/macrophage family of cells that differentiateunder the effect of two requisite cytokines, namelymacrophage colony stimulating factor (M-CSF) and receptoractivator of NF-κB ligand (RANK-L) [81]. GCs increase the expression of M-CSF and RANK-L, anddecrease the expression of its soluble decoy receptor,osteoprotegerin, in stromal and osteoblastic cells [82].

GCs also induce the expression of Interleukin-6, an osteoclastogenic cytokine, and suppress the expressionof interferon-beta, an inhibitor of osteoclastogenesis [83]. GCs decrease the apoptosis of matureosteoclasts [84]. Thus, there is increased formationof osteoclasts with a prolonged life span explaining, at thecellular level, the induce and prolonged bone resorptionobserved in GIO. The direct effects of GCs onosteoclasts also may contribute to an operational decline inosteoblast function during GCs exposure [85].Although the net effect of GCs is to induce osteoclast number, osteoclast function may be temperedwith cells that no longer spread and resorb mineralizedmatrix normally. Osteoblast signals that depend uponnormal osteoclast function could, thus, be impaired [84].However, these novel findings have been challenged bystudies demonstrating a first effect of GCs on cells of the osteoblastic lineage [85]. In accordance withtheir effects on bone resorption, GCs induce the expression of selected matrix metalloproteinases(MMP). Osteoblasts secrete MMP1 or collagenase 1 andMMP13 or collagenase 3, and both cleave type I collagenfibrils at neutral pH [86]. Cortisol induce collagenase3 synthesis by post-transcriptional mechanisms, by regulatingspecific cytosolic RNA binding proteins, and theirbinding to specific RNA sequences [87]. GCs may also have effects on bone remodelling at the basicmulticellular unit (BMU) level, mainly manifested as areduction in wall width (reduced amount of bone formed

per BMU) [88]. In addition, there is some evidence thatincreased resorption depth (increased amount of boneresorbed per BMU) may occur in the early stages of therapy, particularly at high doses of GCs.

Effects of GCs on bone cells mediated by growth factors:

In addition to the direct actions of GCs on bonetarget cells, other effects are mediated by changes in the synthesis, receptor binding or binding proteins of growth factors present in the bone microenvironment.

GCs influence the expression of insulin-like growth factor I. insulin-like growth factor I induce bone formation and the synthesis of type I collagen, and decreases bone collagen degradationand osteoblast apoptosis [90]. GCs suppress insulin-like growth factor I gene transcription, but do not alter insulin-like growth factor I receptornumber or affinity in osteoblasts. GCs decrease insulin-like growth factor II receptor number, but the skeletal functionsof the insulin-like growth factor II receptor have remained elusive [91]. Theactivities of IGFs are regulated by six IGF binding proteins, all of which are expressed by the osteoblast [92].Of these, IGF binding proteins -5 was reported to have anabolic effects forskeletal cells, and its transcription is suppressed by GCs [93]. The inhibition of (IGFBP-5) synthesis by GCs is probably not key to the ultimate effectof GCs on osteoblastic function, because transgenicmice overexpressing IGFBP-5 exhibit low, andnot increased bone formation [94]. The effects of GCs on insulin-like growth factor I expression by the osteoblast arereversed by parathyroid hormone (PTH), an observationthat may help explain why PTH may be effective in thetreatment of GIO [95].

Indirect effects of GCs on bone metabolism:

GCs inhibit ca absorption from the gastrointestinal tract, by opposing (vitamin D) actions, and bydecreasing the expression of specific ca channels in theduodenum [96]. Renal tubular ca reabsorption also is stoped by GCs. As a consequence of theseeffects, secondary hyperparathyroidism could exist in thecontext of GCs use. But a hyperparathyroid statedoes not explain the bone disorder observed in GIO. Mostpatients with GIO do not exhibit serum levels of PTH thatare frankly elevated. Although vertebral and non-vertebralfractures occur in GIO, this condition is related with apreferential loss of cancellous bone, whereas hyperparathyroidism,is related with a preferential loss of corticalbone [97]. Furthemore, bone histomorphometric analysisdemonstrates decrase bone turnover in GIO, in contrast tothe increased bone turnover that characterizes hyperparathyroidism. These observations mark that hyperparathyroidism does not play a central role in thedevelopment of the skeletal manifestations of GIO. Nevertheless,there may be subtle, but important effects of GCs on the secretory dynamics of PTH, with adecrease in the tonic release of PTH and an increase inpulsatile bursts of the hormone [98]. In healthy subjects,PTH is secreted by low amplitude and high frequency

pulses superimposed upon tonic secretion. Pulsatile PTHsecretion may be important for the organizing of the actionsof the hormone on bone [99].

Abnormal PTH pulsatility isfound not only following GCs exposure, but alsoin post-menopausal women and in acromegaly [100].

Moreover, GCs may induce the sensitivity ofskeletal cells to PTH, by increasing the number and affinityof PTH receptors [101].moreover to the direct effects of GCs onskeletal IGF-I, GCs decrease the secretion ofgrowth hormone (GH) and may alter the systemic GH/IGFIaxis [102]. However, serum levels of insulin-like growth factor I are normal inGIO. GH secretion is blunted by GCs by anincrease in hypothalamic somatostatin tone, and GHadministration could reverse some of the negative effectsof chronic GCs treatment on bone [103].Secretion of GH is blunted in asthmatic patients receivinginhaled GCs, suggesting that inhaled steroidsmay alter the synthesis or release of GH [104]. However,the cause or consequence of this effect is not clear, sinceserum levels of cortisol and of IGF-I are not suppressed [104].

GCs inhibit the release of gonadotropins, and as aresult estrogen and testosterone production. This effect of GCs on the gonadal axis may be an additionalfactor playing a role in the pathogenesis of GIO [105].

Prevention and treatment of GIOP

Because the most fast bone loss occurs in the first 6–12months in patients commencing high-dose GCs, it is main to consider two different therapeutic situations:

prevention in patients starting GCs who have not yet lost bone

(2) treatment (or secondary prevention) in patients on

chronic GCs who will generally have some significant degree

of existing GC-related bone loss, with or without fractures.

Current therapeutic approaches to GCs induced bone lossinclude the following:

• induce of the lowest dose possible

• decrase lifestyle risk factors (e.g., smoking and lowdietary calcium intake)

• consider individualized exercise programs with the helpof a physical therapist to prevent muscle loss and falls

• use of agents that have been studied for potential benefit,including antiresorptives (ca , vit. D and its metabolites, calcitonin , hormone replacement therapy, andbisphosphonates) and agents that induce bone formation such as PTHAntiresorptive agents such as the bisphosphonates have generally shown the most consistent efficacy in clinical trials of GIO. Although the effects of GCs on bone formation seemmore important than those on bone resorption, antiresorptiveswill decrase GC effects on bone remodeling and act to preservemicroarchitecture. Bisphosphonates may also act to decrease GCs induced apoptosis. [125]

Hormone Replacement

Hormone replacement therapy is often recommended for GC treated patients, but the evidence supporting its use is limited.

There have been only two controlled trials in men. In a cross-overstudy of 15 men receive chronic GCs for asthma, after 12months, testosterone (250mg/month) increased lumbar BMD by 5 percent compared with the ca group, which had no significantloss. [126]Similarly, testosterone was superior to both nandroloneand placebo in a trial of 51 men increasing lumbar BMD by (5.6%) over 12 months. [127]In a randomized controlled trial in postmenopausal women with rheumatoid arthritis, which contain a subgroup receiving chronic low-dose GCs, estrogen increased lumbarBMD by (3.8%) during 2 years compared with (0.6%) loss in thecalcium-treated control group. [128]In a retrospective study, examining postmenopausal women treated with prednisone, spinalBMD was significantly higher in those women who were givenestrogen and progesterone replacement compared with those notreceiving hormone replacement. [129]

Calcium and Vitamin D

With respect to ca , several studies suggest a benefit of ca supplementation for secondary prevention in patientsreceiving chronic low dose GCs. However, primary preventiontrials in patients starting GCs, where ca alone was used inthe control arm, have observed rapid rates of loss. [130]It is

therefore likely that ca alone is not enough to preventrapid bone loss in most patients starting high dose GCs.Ca is often used in combination with vit. D in GIObased on older studies that measured only forearm bone massand studied patients on chronic GC treatment. [131]In a primaryprevention study comparing 1000 mg calcium daily plus50,000 U vitamin D weekly against placebo over 3 years in 62patients starting GCs, bone loss at the lumbar spine was notsignificantly different between ca plus vit. D groupand placebo. However, a secondary prevention study in patients receiving chronic low dose GCs for rheumatoid arthritis [132]observed an annual spinal loss of (2.0%) in placebo treatedpatients compared with (0.7%) gain in ca/vit.D 3 treated patients (1000 mg plus 500 IU/day, respectively).Vit.D is sometimes used to refer to both the calciferolsand active metabolites, but they have different therapeuticeffects. The most commonly used active hormonal forms of vit.D are calcitriol (1,25-dihydroxyvitamin D) and alfacalcidol (1 alpha -hydroxyvitamin D). One study examined the effect of (12 months of calcium, calcitriol, or calcitonin in 103 patients starting GCs). Patients treated with ca lost bonerapidly at the lumbar spine (4.3% in the first year), whereaspatients treated with either calcitriol or calcitriol plus calcitoninlost at a much decrase rate (?1.3% and ?0.2% per year,respectively). Both groups were significantly different from the ca group. Another randomized double blind controlledtrial in 145 patients starting GCs compared alfacalcidol withcalcium. [133]After 12 months, the change in spinal BMD withalfacalcidol was (+0.4%) compared with (-5.7%) with ca.

Hypercalcemia occurred in only (6.7%) of alfacalcidol-treatedpatients [134]compared with (25%) with calcitriol. [135]Whetheractive vit.D metabolites have any advantage over simple vit.D in the treatment of established GIO remains controversial with both + and – studies. [136]

Calcitonin

In patients receiving chronic GCs, salmon calcitonin hasbeen reported to improve forearm bone mass in chronic obstructive lung disease, attenuate vertebral bone loss in sarcoidosis, and increase lumbar BMD in asthmatics. [137]Calcitoninhas been studied in more recent trials in patients startingGCs. [138]In two primary prevention studies, there was atrend but no statistically significant additional benefit of addingcalcitonin to calcitriol or cholecalciferol.

Bisphosphonates

The first proper trial of bisphosphonates in GIO was with anoral formulation of pamidronate. [139]Since then, numerous trialshave examined the efficacy of bisphosphonates on GC-inducedbone loss with positive results. In a primary prevention study of 141 patients commencing GCs who received prophylaxis witheither cyclical etidronate or (500 mg) of ca , mean lumbar BMD change with etidronate was (+0.6%) compared with(-3.2%) in the ca group at the end of 12 months. Forpostmenopausal women only, there was a significant differencein the incidence of new vertebral fractures favoring etidronate (21.9% versus 3.2%). In a secondary prevention study in 37postmenopausal women who received GCs for at least 3months, the mean change in lumbar BMD was (+4.9%) withetidronate versus (-2.4%) with placebo over 2 years, which wasstatistically significant. [140]

There were no statistically significant differences for the femoral neck BMD or serum andurinary markers of turnover.

The common results of two trials with alendronate in (477GC )treated subjects who also received prophylaxis with ca/vit.D (800–1000 mg/daily plus 250–500 IU/daily, respectively) have been reported. 34 Patients were stratified according to their period of prior GC treatment. Over 12months of follow up, the important change in lumbar spine BMD inpatients who received GCs for <4 months was (+3.0%) foralendronate (10 mg/day) compared with (-1%) in the placebogroup. In those who had received chronic GCs (>12 months),the increase with alendronate was (+2.8%) but also was (+0.2%) for ca . These latter data suggest ca/vit.D is ableto prevent further bone loss in patients on chronic low dose GCs secondary prevention.

(Figure9):Algorithm for the diagnosis and management ofGIO.

A posthoc analysis of incidentvertebral fractures favored alendronate in postmenopausalwomen (13% versus 4.4%). The effect of alendronate on bone

histomorphometry has been assessed in 88 patients (52 womenand 36 men, 22–75 years of age) from the above studies. [141]

Iliac bone biopsy specimens were obtained after tetracyclinedouble labeling at the end of the first year of therapy. Osteoidthickness and volume were significantly lower in alendronatetreated patients, irrespective of the dose; however, mineralapposition rate was not altered. Significant decreases of mineralizing surfaces, activation frequency, and bone formationrate were also noted with alendronate treatment.

The results of a primary prevention trial with risedronatecompared with ca (500 mg/daily) in 224 GCs treated subjects have been reported. Risedronate (5 mg/daily) preventedspinal bone loss (+0.6%) compared with ca (-2.8%)over 12 months. Incident vertebral fracture rates were (17.3%) with ca and (5.7%) for risedronate (5 mg) (p = 0.072).Vertebral fractures were only seen in postmenopausal womenand men but not in premenopausal women. The effects ofrisedronate in 290 patients receiving chronic GC treatment(prednisone > 7.5 mg/day for >6 months) have also beenreported. Approximately 33% of patients had vertebralfractures at baseline. The control group, who were treated with ca (1000 mg) and vit.D (400 IU/daily), maintained astable BMD over 12 months. However, treatment with risedronate (5 mg/day) significantly increased lumbar spine (+2.9%)and femoral neck (+1.8%) BMD. A pooling of the risedronateprevention and treatment studies showed a significant reduction

in vertebral fractures after 1 year. [142]

Intermittent intravenous pamidronate and ibandronate havehas also been reported as effective alternatives to oral bisphosphonates in GIO.

PTH

PTH has the potential to increase osteoblast numbers by increasing both their replication rate and by decreasing apoptosis. Arandomized controlled trial of PTH performed in postmenopausalwomen with GIO [143] reported that patients treated with PTH andestrogenhadsignificantincreasesinbonemass(+35%forlumbarspine by QCT, (+11%) for lumbar spine by DXA, 1% hip) after 12months , withnochangesobservedintheestrogenalonegroup.Allstudy patients were followed for an additional year after the PTHwas discontinued, and total hip and femoral neck bone massincreased (~5%)above baseline levels. [144] Treatment with PTHresulted in a dramatic increase in biochemical markers of boneturnover. Osteocalcin increased (>150%) above baseline levelswithin 1 month of starting the therapy and remained elevated forthe remainder of the treatment period. Bone resorption increasedto the same levels as osteocalcin after 6 months of therapy. Thestudy was not powered to determine if PTH could reduce newvertebral fractures in GIO.

Monitoring of therapy

The role of monitoring the effects of bone sparing agentsin GIOP, using either BMD or biochemical markers of boneturnover, has not been determined. Depending on the rate ofbone loss prior to treatment, significant treatment responsesin individuals may be detectable within 1 to 2 years usingdual energy X-ray absorptiometric measurements of bonedensity. However, in individuals taking high doses of GCs , large changes in BMD may be detectable earlierand measurement at 6 months may be appropriate. The spineis the preferred site for monitoring because of the low preci sion error of bone density measurements at this site. Boneloss from the spine during the first year of glucocorticoidtherapy may vary between (3% and 10%); since the precision error of measurements is approximately (1%) , a loss ofmore than (3%) (the least significant change) is likely to besignificant. Rates of bone loss are less during establishedglucocorticoid therapy and in this situation the target is toincrease BMD above the least significant change, ie, anincrease of more than (3%). Bone resorption markers, suchas N-telopeptide or C-telopeptide of type I collagen, show similar changes with treatment in individuals takingglucocorticoids to those in women with postmenopausalosteoporosis. However, bone resorption markers may alsobe affected by changes in inflammatory activity and hence adecrease following initiation of GCs therapy mayreflect suppression of disease activity rather than reducedbone resorption. [22]

There are many recommendations for the prevention andtreatment of GIOP. Here we describe the most important.

Conclusion

Glucocorticoids are widely used to treat a number of medical disorders. The administration of oral glucocorticoids isassociated with a significant increase in fracture risk at thehip and spine. Measurement of BMD using dual energy x-rayabsorptiometry is currently recommended for assessmentof fracture risk in individuals treated with glucocorticoids.

In general, the pharmacological agents that have undergoneassessment for the prevention and treatment of GIOP aresimilar to those used for postmenopausal osteoporosis. But,according to character of GIOP, the indications for treatment have to be earlier in comparison with postmenopausalosteoporosis.

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