Re) Open emar ee To cle: Bit K, Roux € Glucocoticid-induced osteoporosis. AMD Open 20152000018 oi 10.1136rmdopen-2014- oon >» Prepublaion history for this paper is avaiable online To view these les please vist the journal onine (htp:6x. doi org/10.11960 mdopen-2014-000014) Received 12 Februay 2015, Fevisedl 16 March 2015 Aesepied 17 March 2015 ® CrossMark Deparment of ‘Rneumatology, Research Contr, Epidemiology and Biostatistics Sorbonne Pais (te, Cochin Hosp, INSERM U1, Pars Descartes University, Pars, France Prcessoe Cvisan Roux; chitin rouxtech app fr REVIEW Glucocorticoid-induced osteoporosis Karine Briot, Christian Roux ABSTRACT Corticosteroid induced osteoporosis is the most comman ‘orm of secondary osteoporosis andthe frst cause in yung people. Bone loss and increased rate of fractures ‘ccur early after the initiation of corticosteroid therapy, ‘and are then related to dosage and treatment duration “The increase in fracture risk isnot fully assessed by bone mineral density measurements, as itis also related to ateraion of bone qualty and increased risk of fas. In pation with rheumatoid ath, a reat to target stratogy focusing on low disease activity including through the use ot low dose of prison, isa key determinant of bone loss prevention. Bone loss magnitude is variable and ‘there is no clearly identified predictor ofthe individual risk of fracture, Prevention or treatment of osteoporosis ‘shouldbe considered in ll patents wo receive prednisone. Bisphosphonates and the anabolic agent Parathyroid hormone (1-34) have shovm tei efficacy in ‘the treatment of corticosteroid-nduced asteaporass Recent international quidelines are available and should ‘guide management of corticosterid-induced osteoporosis, which remains under-diagnosed and under- ‘treated, Duration of antiosteoporotc treatment should be discussed a the individual level, depending on the ‘subject's characteristics and onthe underying inflammation evolution. INTRODUCTION Glucocorticoid-induced osteoporosis (GIOP) is the most common cause of secondary ‘osteoporosis, the first cause before 50 years and the first iatrogenic cause of the disease." Prior and current exposure to glucocorté- ‘coids (GCs) increases the risk of fracture and bone loss. A key point is that the underlying inflammation for which GCs are used also has a role in bone fragility, as there is a strong relationship between inflammatory cells and bone cells.” This is one of the determinants of rapid bone loss occurring at the of GCs, The prevalence of use of oral GCs in th ‘community population is between 0.5 and 0.9% (65% women), rising to 27% in won aged 250 years.”” In the Global Longitudinal Study” of Osteoporosis in Women (GLOW), ‘conducted in 10 countries, .6% of 60 898 post. menopausal women were receiving GCs at haseline visit” ‘The main canses of GC use are > Glucocorticod-induced osteoporosis (GIOP) is the most common cause of secondary osteopor- ‘sis, the most common cause before 50 years ‘of age, and the most common iatrogenic cause ofthe disease. » Previous and current exposure to glucocort- colds (GCs) increases the risk of fracture and boone loss. > The increase in fracture risk isnot fully assessed bby bone mineral density measurements, as it is also related to alteration in bone quality and increased risk of falls. > Prevention or treatment of osteoporosis should ‘be considered in all patents who receive GCs. > Recent international guidelines are available and should guide management of corticosteroid ‘induced osteoporosis, which remains under- iagnosed and under-treated. inflammatory rheumatic disorders (rheuma- oid arthritis, polymyalgia rheumatic...) and lung disorders (asthma and chronic obstructive lung diseases). Apart fom bone and ocular side effects, ipochstrophy and neuropsychiatric disorders are also common adverse events of long-term GC therapy.’ A number of guidelines for GIOP are now available, but the proportion of GCareated patients receiving preventatives for bone com: plications remains low, Paradoxically, the numbers of underlying comorbidities and con- comitant treatments are strong determinants of the absence of prevention of GIOP, although, they are themselves adided risk factors for osteo porosis’""' There has been greater awareness of this condition in recent years, with improve- ment in the number of patients receiving bisphosphonates, even interven: tions by pharmacist do not significantly improve these numbers," and recent studies confirm the neglecting of osteoporosis prophy: laxis in patients exposed to GCs. However, PATHOGENESIS Bone fragility in GIOP is characterised by dity of bone loss at the introduction of BM) Brot K tat AMD Open 2016:18000014, do 40.1136/mdopen-2014-000014 eular ' :yBLAdoo Kq paroaroie son6 Aq 2Z02 “6 YO!EWN Uo /WU09 Tue: vadopUN)'d)\| WOH paPEOIUMER “sLOZ LudY g UO 71 0000-rL0z-UadopUY/gEL 0} Se paysiIand ysiy ado GWGees GCs, and the discrepancy between bone mineral density (BMD) and risk of fractures. These two points can be explained by the pathogenesis of GIOP. Role of underlying inflammation In the general population, even small elevations of © reactive protein within the normal range increase non- traumatic fracture risk.'' In some studies, variations within the low levels of inflammatory markers and cyto- Kines predict bone loss and elevated inflammatory markers are prognostic for fractures."” Rheumatoid arthritis (RA) doubles the risk of hip and vertebral fractures, regardless of the use of GCs,"” and disease activity is consistently associated with low BMD. In a prospective study of patients with early RA con- ducted at a time when biotherapies were not available, high bone loss was observed, mainly in patients with per- sistent inflammation during follow-up (ie, persistent high CRP)."" In ankylosing spondylitis, an inflammatory disease in which GCs are not used, there is bone loss andl an increased risk of vertebral fractures, driven by nation," ‘There is a strong biological rationale for these clinical observations, Osteoclastogenesis is under the control of RANK.ligand, which is produced by osteocytes in nor bone remodelling, but also by lymphocytes and fibro- blasts in other situations, sueh as oestrogen deficiency"! and inflammation, Osteoclastogenesis can be enhanced by a number of cytokines, the main pathway being driven by Th 17 cells subpopulation (ie, interleukin (IL) 6 and IL23)."*" Tumour necrosis factor a (TNF-c) transgenic mice are models of osteoporosis with dra- matic decrease in bone mass and deterioration of bor microarchitecture. Moreover, an over expression of scl ‘ostin has been observed in these models, with a conse- quence of inflammation-related decrease in bor formation.”’ Finally autoimmunity has a role in bone remodelling, as antibodies against citrullinated proteins (ACPAs) can increase osteoclast numbers and. activity through citrullinated vimentin located at the surface of ud cells (through a TNF-a local effect). clinical observations and biological st inflammation has a deleterious eflect on bor remodelling, inducing an increase in resorption and a decrease in formation, before effect of GCs the Bone effects of GCs. predominant effect of GCs on bone is the impair- ment in bone formation (figure 1).”" The evidence that this is a direct effect, independent of the inflammation effect, comes from studies conducted in healthy volu img daily is enough to rapidly and sig. nificantly decrease serum PINP and osteocalcin, which are specific markers of bone formation; the changes are reversed after diseontiny: a [EXCESS OF Glucocorticoids |] — J =—__.n. | ene quality Tone mace Increasearishoffactre ae Uris ott ea craneeandtnscoimertome | | cactemmaten mee a, | ee thenaancace ra SareoerTes || osTeoausaTs coreoeusTs || aS, | vsecumein Tranton —Vomeeneaton Totton |_{1orars ees teqete Nemes Vives tives — Figure 1 Pathophysiology of glucocorticoid-induced osteoporosis (adapted from ref *), z ‘riot K eral AMD Open 2016; =000014,do10.11a6/mdopen 2014 000014 YBAdoo Aq parpayoig sanb Aq zz0z “6 YoEWN UO /Wu09 Tusa vadopuLH)'dyy WON papEo|UMEG "sLOz Udy g UO »/.0000-r10z-UadopUH/ge! 0} Se PaYsiIand sil :YadO GNGCs at high concentrations dramatically decrease bone formation rate, osteoblast numbers, and osteocyte numbers and activity."“"* The decrease in osteoblast differentiation includes induction of adipogenetic tran- scription factors (PPARy) and suppression of Wnt protein signalling:’'”” the increase of osteoblast and ‘osteocyte apoptosis is associated with caspase 3 activ tion,” Moreover, the osteoblast function is decreased through the antianabolic effects of GCs, such as decrease in GH, IGP1 and IGFBPs4:. In contrast, GCs increase IGFBP, transcription thus decreasing IGF2, another local regulacor of osteoblast function. GCs are associated with a dec 1g chat ‘matrix properties surrounding the osteocyte lacunae. GCs increase the expression of RANKigand decrease the expression of osteoprotegerin and osteoblastic cells.”” As a conse lifespan of osteoclasts is observed (co decrease in the lifespan of osteoblasts). Although this increased resorption has been demonstrated, much of the Gi loss is caused by the reduced bone which persists throughout GC case in osteocyte viability, inch related bon Indirect effects of GCs phasis had been placed on the effects of fon calcium metabolism, because of decrease of gastrointestinal absorption of calcium and induction of renal calcium loss. A secondary hyperparathyroid- ism has been suggested as a determinant of bone effects, Actually, there is no evidence for elevated endogenous levels of PTH in these patients and histo- logical features are not those related to an increased PTH secretion."” GCs reduce production of sex steroid hormones, and hypogonadism can by itself induce increased bone resorption.” Glucocorticoid-induced myopathy is related to a direct effect on muscle mass and muscle force; muscle weak- fractures in these patients.” Differential sensitivity to GCs There is great variability of side effects of GCs among individuals, including bone loss, for largely unknown, reasons. Attention has been paid to the 1 phydroxysteroid dehydrogenase (11f4H1SD) ystem, which is a prereceptor ‘modulator of GC action, This system catalyses the intercon- version of active sone, and the 11BHSDI 1 amplifies signalling in osteoblasts, Interestingly, BILHSD, widely expressed in GC target uding bone, can be modulated and amplified by proinflammatory eytokines,"" “age and GC administra- tion ise nechanism could be a key regulator of the effects of GCs on bon sitivity can also be regulated by polymorphisins in the GC receptor gene." Individual GC sen- EPIDEMIOLOGY ‘The risk of fractures is increased by twofold in patients with GCs, and the risk of vertebral fractures is even higher. In a study comparing 244 235 oral GC users and 244 235 controls, the risk of hip fracture is 1.6, and that of vertebral fracture is 2.6; these numbers have been reproduced in many studies." The global prevalence of fractures in patients receiving longterm GCs has been reported to be 30-50%. In 551 patients receiving long-term GCs, the prevalence of vertebral fractures was, 37%, with 14% of patients having 2 or more asymptor atic vertebral fractures; 48% of patients aged >70 and 30% of those aged <60 years had at least one VE" 1e prevalence increases with age, a key point for pre- ventive strategies. A number of studlies are re help to identi ‘obser 1s from epidemiological want for elinical practice, as they could a high-risk group of pat Time effect The increase in fracture risk is. immedia Smonths after the initiation of therapy and reverses sharply after discontinuation of GCs." This cannot be explained by BMD changes, but can be related 10 the added effects of GCs on bone remodelling. previously uncoupled by the inflammation itself, and the dramatic effect on bone strength through induced apoptosis. of osteocytes. Data also suggest a rapid increase in rate of falls after start of oral GCs." Thus primary prevention, after carefual assessment of the fracture risk, is recon ‘mended in high-risk patients fas early as, Dose effect In epidemiological studies, the increased risk of frac- tures is observed even at low doses of prednisone, that is, 25-5 mg per day. The appropriate care of patients receiving such low doses is not well defined. There is a dosedependent increase in fracture — incidence. Interestingly, the fracture risk is related to the current daily dose, more than to the cumulative dose;"* this may be related to the difficulty of an accurate calculation of this cumutative dose. Prior versus current GCs use Ever use of GCs is associated with an increased risk of hip fracture, and this justifies the assessment of osteopor- ‘osis and fracture risk in all patients. However, the risk is mainly associated with recent and prolonged GC us more than to remote or short courses.” BMD loss BMD loss is an immediat tion of GCs and affects th more than it does the cortical bone (ie, femur). According toa meta-analysis of 56 crosssectia nd 10 longi- tudinal studies, bone loss assessed by dual-energy X-ray absorptiometry, can be 5-15% during the first year of treat- ment." determinant of BMD at any time is the nce of the introdu bone (ie, spine) ‘Brot K etal AMD Open 201512000014, do 10.1136/imdopen-207¢-o00074 :yBLAdoo Kq paroaroie son6 Aq 2Z02 “6 YO!EWN Uo /WU09 Tue: vadopUN)'d)\| WOH paPEOIUMER “sLOZ LudY g UO 71 0000-rL0z-UadopUY/gEL 0} Se paysiIand ysiy ado GWcumulative dose. The increased rate of bone loss persists in chronic GC users, but more slowly. ASSESSMENT OF FRACTURE RISK Role of BMD There isa mismatch between BMD data and fracture data in patients receiving GCs because of the disparity related to the alteration of bone quality. At similar levels of BMD, postmenopausal women taking GCs have considerably higher risk of fracture than controls not using GCs, There isa debate on the appropriate Tscore threshold to bbe considered a risk and asan indication for treatment in, patients with GCs: the same diagnostic criterion as in postmenopausal women has been suggested (T<=2.5),"" but a higher threshold (ie, TS=1.5) has been proposed for intervention,"” because bone loss can be 10% or more in some individuals over the first year of GC use, There is no means to provide an evidence-based thresh- old for treatment decisions. A practical approach is to ree- ‘ommend a BMD measurement in GC users (optimally at the initiation of treatment) and to consider that patients with T <-2.5 as those who should receive the highest pri- rity for treatment.” However, beyond the BMD, a more comprehensive approach of the risk and clinical judge- ment is needed. Role of FRAX ‘The WHO fracture risk assessment tool (FRAX) algo- rithm has been developed to estimate the 10-year risk of hip and other major fractures (clinical spine, humerus or wrist fracture) based on clinical risk factors, with or without BMD.” The risk factors included in FRAX are: age, sex, body mass index (BMD, personal history of frac- ture, parental history of hip fracture, current smoking, aleohol intake, glucocorticoid use, rheumatoid arthritis, other causes of secondary osteoporosis and femoral neck {not spine) BMD. These clinical risk factors are largely independent of BMD and can thus improve the fracture risk assessment, FRAX cannot be used in premenopausal women, men aged <40 years and in subjects previously treated with antiosteoporotic drugs. (One of the limitations of FRAX is that use of oral GCs is entered as a dichotomous tisk factor and does not take into account the dose of GCs and the duration of use, Moreover, FRAX does not take into account the differ ence in risk between prior and current use." FRAX assumes an average dose of prednisolone (2.5+7.5 mg/ day or its equivalent) and may underestimate fracture risk in patients taking higher doses and may overest risk in those taking lower doses. Moreover the predictive value of FRAX has been mainly validated for non- vertebral fractures although the principal risk in GCs users is for vertebral fractures. Adjustment of FRAX has been proposed for postmenopausal women and men, aged 250 years with Iower or higher doses than 7.5 mg/day: a factor of 08 for low-dose exposure and 5 for highlose exposure for major osteoporotic fractures, and 0.65 and 1.20 for hip fracture probability:”” For very high doses of glucocorticoids, greater upward adjustment of fracture probability may be required. FRAX assessment has already been included in some guidelines at different steps of the treatment decision, American College of Rheumatology guidelines recom: mend treatment in postmenopausal nd men aged 50 years or older starting oral glucocorticoids with a FRAX-derived 10year probability of major osteo porotic fracture of over 10%, and in those with a probe ability of less than 10% if the daily dose of prednisolo or its equivalent is 27.5 mg/day."’ According to the International Osteoporosis Calcified Tissue Society” recommer decision for postmenopausal women and for m 50 years exposed 10 ofal glucocorticoids far 23 months should be based on fracture risk assessment with FRAX. adjusted for glucocorticoid use (with or without BMD testing). Treatment can be considered directly (without FRAX assessment) if patients are at high risk defined by one of the following criteria: prevalent fracture, age 270 years, exposure to a glucocorticoid dose 27.5 mg per day or low BMD (I-25). Role of underlying disease Persistent i ation is associated with bone loss as shown in longitudinal studies in patients with active RA or ankylosing spondylitis (SpA). In contrast, prospective ‘open studies show that complete control of inflamm tion (in parallel with clinical improvement and th increased mobility) is accompanied by the absence of bone loss.”” This is expected in SpA in the absence of GCs, but is also observed in RA of the hand, spine ar hip, in patients receiving low doses of GCs."""" In d BeSt study, conducted inpatients with recentonset active RA, bone loss was limited in all treated groups, including in the group initially treated with high-dose prednisone.” Thus, the concept that a high level of inflammation is more deleterious for bone than a low dose of GCs, controlling this inflammation is relevant as far as surrogate markers (BMD, biological parameters) are concerned. However, there is no evidence for a reduction in fracture risk with such a strategy.” and new epidemiological studies are mandatory in this matter. Role of patient characteristics Age, female gender, low BMI, history of falls and previ- ous fractures, duration of menopause and smoking are associated with fracture risk in patients with GCs, simi- larly to how they are in primary osteoporosis. We have shown that prevalence of nonvertebral fractures is a strong determinant of the risk of having vertebral frac- ues in patients with RA,” implying skeleton is already of inadequate strength to withstand the ‘of daily living. Beyond GC use, these risk factors must be assessed in all patients, and all causes off added risk factors of fractures the individual's secondary osteoporosis in patients with GCs, ‘riot K eral AMD Open 2016; =000014,do10.11a6/mdopen 2014 000014 :yBLAdoo Kq paroaroie son6 Aq 2Z02 “6 YO!EWN Uo /WU09 Tue: vadopUN)'d)\| WOH paPEOIUMER “sLOZ LudY g UO 71 0000-rL0z-UadopUY/gEL 0} Se paysiIand ysiy ado GWTREATMENT General measures At the initiation of GC weatment, the patient's height ‘must be measured, as height loss in the follow-up could be related to asymptomatie vertebral fractures. Biological tests are performed to screen for other causes of bone diseases. There is no indication for assessment of bio- chemical markers of bone remodelling either at baseline or during follow-up, as bone turnover is consistently low in GC users [As the daily dose of GCs is a determinant of fracture risk, it must be constantly reviewed by considering both the reduction of the dose to the minimally act native administration such as intraarticular injection: ‘The tisk of falling should be assessed in particular in elderly patients, patients with painful joints of the lower limbs and patients with massive doses of GCs. Physic activity oF lapted to the underlying condition. ‘Attention to nutrition must be paid to prevent protein sand calcium intake deficiencies. nD have been used for decades in GIOP, although there are controversies about their effet on BMD. In 66 patients with RA receiving prednisone, 1000 mg/day of calciun carbonate and 500 1U/day of vitamin Ds induced a posi tive change of 0.68% per year at the lumbar spine, versu a decrease of 1.31% per year in the placebo groups there vwas no effect at the femoral neck No benefit was observed in another study with a $year followup.’” However, itis reasonable to consider that any deficieney n and vitamin D could be deleterious in patients ng oF receiving GCs, For calcium, the recommen- dation is to have an intake of 1000-1500 mg/day, and supplementation should be prescribed only to patients whose dietary intake does not provide this adequate quantity. GCareated patients may seldom be outdoors, and thus exposed more than the general population to vitamin D deficiency. Supplementation is adequate between 800 and 2000 IU per day. There is no evidence of an advantage using caleitriol or alealcidol, as there is large variability of outcomes with these vitamin D meta- bolites over plain vitamin D. iobilisation should be considered, Pharmacological treatment Bisphosphonates and teriparatide have been assessed in prevention and treatment of GIOP. There are a number Of issues regarding their efficacy. Fracture incidence has not been a primary end point of any study (the end point being BMD), the duration of the studies is low (1 year on average) and the number of men and premenopausal women in these studies is low: Thus the efficacy on frac- tures is mainly based on bridging data between the short term change in BMD in patients with GCs, and the long- term change in BMD and reduction of fracture risk in patients with postmenopausal osteoporosis, Bisphosphonates are the more popular antiosteoporo- tic drugs. Alendronate (oral 5 or 10mg once daily, or 70mg once weekly), risedronate (oral Smg daily or 35 mg one weekly) and zoledronate (intravenous infusion 5 mg once yearly) prevent bone loss at the spine and hip in patients initiating GCs, and increase BMD in patients on longterm GCs. Alendronate was assessed in a placebo controlled study in 477 men and women over 48 weeks. ‘There was a 2.1 and 2.9% inerease at the lumbar spine the 5 and 10mg alendronate groups, respectively and a 0.4% decrease in the placcbo group. At the femoral neck the changes were +1, +12 and —1.2%, respectively Interestingly the decrease of BMD in the placebo group (receiving calcium and vitamin D) was driven by the dur- ation of GCs: -2.9, —1.4, +08 in patients receiving GCs for less than 4 months, 4 12 months, respectively." In a followup study in a second performed in 208 out of the 477 patients, there we ewer patients with new vertebral fr group (0.7%) than in the placebo group (6.8%). LLyear studies were pet i prevention in ps ment of GIOP nn pooling these two st of fractures in the first year of therapy: 16% of placebo patients and 5% of those on risedronate 5 mg/day." Inacompar ed study, soled nie aciel (I injection) induced a higher BMD increase than risedronate (daily) in treatment (44.06 vs 42.71%) and prevention (42.6 ys 0.6%) subgroups over I year at the lumbar spine.” Attention has been paid recently to osteonecrosis of the jaw and atypical femoral fractures such as side effect of ong vion of antireyorptive drags in ‘osteoporosis; these events are very rare,” ”! but GC use is fone of the identified risk factors. Buccal hygiene proce- dures should be implemented to prevent any local increased risk of infection. Whether these rare events can change the duration of anti-resorptive treatments in long- term GG users needs further studies. Bisphosphonates should be used cautiously in premenopausal women, as they cross the placenta; appropriate contraception must be used if necessary and preference given to a short bone halblife bisphosphonate The use of administrative databases offers the oppor tunity to assess a huge number of patients, taking into account the methodological issues related to these studies (retrospective design, lack of details in_patic characteristics, absence of confirmation of the diagnosis of fractures, etc). ‘Two welkdesigned studies with such an approach, suggest the efficacy of bisphosphonates. in reducing fractures and a better efficacy when the antios: teoporosis medic wing within 90 days. of chronic GC wse, reaching a 48% reduction rate of frac ture.” However, not all studies support these conch sions, and there is still a discon and improvement of outcomes." ‘There is so far no study of denosumab on GIOP. In a subgroup analysis ofa 12month study of patients with RA (still active although they were receiving methotrexate) treated with denosumab, BMD increases were similar in 12months and more than sures i ormed with riseds weet between GIOP cat ‘Brot K etal AMD Open 201512000014, do 10.1136/imdopen-207¢-o00074 :yBLAdoo Kq paroaroie son6 Aq 2Z02 “6 YO!EWN Uo /WU09 Tue: vadopUN)'d)\| WOH paPEOIUMER “sLOZ LudY g UO 71 0000-rL0z-UadopUY/gEL 0} Se paysiIand ysiy ado GWpatients with and without GCs.” Such data are relevant for use of denosumab in patients with contraindications for bisphosphonates, such as renal insufficiency. GIOP is a condition where the principal cause of bone loss is reduction in bone formation. This is the rationale for using teriparatide, a parathyroid hormone peptide pro- ducing anabolic skeletal effects by stimulation of bone for. mation, In a I8month randomised tial conducted in patients with GOP, teriparatide 20 jig daily was compared to alendronate 10mg daily; as expected, the inerease in BMD was higher with the anabolic agent as compared to the antiresorptive one (7.2% vs 3.4% at the lumbar spine). More importantly, a significantly lower number of verte- bral fractures was observed: 0.6% and 6.1% in the teripara- tide and alendronate groups, respectively.” 77 Data we confirmed over 36 months. ‘There are a number of guidelines published by different national societies and colleges, on use of pharmacological treatment in GIOP, which vary somesshat."" 7"? However all of them stress the early increase in the risk of fracture at the i fon of glucocorticoids, and the importance of recognition of patients at high risk of fracture; for such patients (elderly subjects, already osteoporotic patients, those on high doses of GOs), primary prevention using bisphosphonates is abvays recommended. Follow-up Adherence to antiosteoporotic treatment may be low in some patients who are already taking multiple medica- tions, and should be assessed regularly. Height loss can be related to vertebral fractures, sometimes asymptom- aie because of the analgaesic property of no guideline about the use of BMD m s. There is aasurement; in Clinical practice it could be useful to check for any bone loss 1 of 2 years after initiation of weatment CONCLUSION We should not go on neglecting fracture risk in_ patients with GCs. This risk must be assessed in all patients at the initiation of prolonged GC therapy. The treattotarget strategy focusing on low disease activity is effective on bone loss in RA. New epidemiological data are needed (0 assess the benefit of such a strategy on fracture incidence. Competing interests None Provenance and peer review Commissioned; eternal peer reviewed Data sharing statement No addtional data ar avaiable ‘Open Access This isan Open Access arte distributed in accordance with the Crate Commons Atribution Non Commercial (0 BY-NC 4.0) license ‘hich permits oters to distbut, remix, adap, bul upon this work non commercially, and eense thet derivative works on different terms, provided the original work is propery cited an the uses non-commercial. See ftp. ‘reatecommons orgicensesby-nl40/ REFERENCES 1. Kak C, Sambrook PN. Secondary osteoporeis in patients with an osteoporotic facture. Best Pract Res Cin AeuraioN '2009'28:700-79, 2. Rawk C. Osteoporosis in inammatary jit ciseazes. Ostogporos It povnzaa1-3, 3. Soucy E, Bolamy N, Adachi JD, eal A Canadian survey on the ‘management of coficosterid induced osteoporosis by ‘heumatdogists. J Rheumatol 2000-27:1506-12. 4, Farde , Petersen, Nazareth |. Prevalones of lang term ora ‘lucecaticas presciptons inthe UK over the past 20 oars. Freumatlogy (Oxtord) 2011;50:1982-0. 5. Overman AA, Yeh JY, Deal CL. Provalance of cral lucecorid ‘usage inthe United Siates: a general population perspective ‘A Gare Res 2013:65°294-8. 6, Diez Perez A Hooven FH, Adachi JD, ota Regional tlerences in tteatment for osteopoross. The Gobal Longitudinal Study of Osteoporosis n Women (GLOW), Bone 2041 49:498-8. 7. Sivermann 5, Curt J, Saag K, etal Inematonal management ot ‘bone heath in glucccoricod-exposed icviduni inthe ebservatonal GLOW stu. Ostecpores In 2015,26:419-20. 8. Foldtin AC, Elmer PJ, Nichols GA. ofa racic patos in patente rik or ueseorieae.indueed asteoporosis. Osiogporae fn 2005;16:2168-74 9. Guzman-Ciark JR, Fang MA, Sehl ME, etal. Bares inthe ‘management of lucocoricosnduced osteoporosis. Ais ‘Broun 2007 575140-6 10. Soloman DH, Katz JN Jacobs JP, ef ak Management of cocorticoKdinduced osteoporesis n patents with heumatois Stns ates and predictors of care in an acadomic mheumatology practice, Ais Pheu 200846:3136-42 11, Yood RA, Harold LR, Fish Lo al Prevention of lucocortiold- Induced ostoopaosis. Ar inter Mee 200116113227 12, Duyendak Mi Naurion M, Athotar J, etal Coricstered-nduced costeopoross proven: longtudial practee pattems in The NNotnerands 2001-2008. Ostooporos nt 2007:18 1429-3, 19. Klop C, de Ves F, inks T, eta lnrease in propyl of cocortcodnduced osteoporsis by pharmacist feedback: 4 randomized contoled tal: Osiegpovs In 2014:25:985-92, 14, Schott Kise, Wegor S, ef al High-sensity C-eacive protein and sk of non trauma actos inthe Brunock sty Jaren inter Ned 2008:166:2495-501 15. Ding, Parameswaran V, Udayan Feta Circulating levels of inflammatory markors predict change in bore mineral dansity and resorption i odor adult: a longitudinal study J Circa Enaoeriot Meteo 2008;80:1852-8, 16, Cauley JA, Danslson ME, Boudreau RM, e a, forthe Heath ABC study. Iitammalory makers and inden fracture risk in oder men land wornen: te Health Aging and Body Composition Study. J Bone Minor Ros 200722108825. 17, van Siaa TP, Geusens P Bisma JW, etal Cnrical assessment of the longtrm risk of tacturein paints with rheumaod aris ‘Avis Ahou 200854310412, 18. Gough AK Lilley J, Eyre S, eta. Generalised bone los in patents with eany eneumatoid aris. Lance! 1998:948 29-7. 19, Malleer JF, Aho LS, E! Maghraoui A, ef al, Changes in bone density in patents wih ankylosing spondylitis: a two-year olow-up suay. Osteoporas In 2001 12:605-8. 20, Brot K, Oumez A. Patemote S, ef al Bone oedema on Mis highly associated wih iw bone mineral density in patients wih early intammatoy back pain results ftom the DESI cohort. Ann Rheur Ds 2013:72-1914-10, 21. Charactcharoonuthaya N, Kosa S, Atkinson EJ, at a Effect Of blockade of TNF ana interaukine-1 ation an bene resorpon in erly postmenopausal women. J Bone Niner Fes 2007-22: 724-8 22, Kong VY, Feige U, Saros | fa Activated T calls reguate bone loss and joint dstructon in acjuvant ats tough osteoprotegerin igand. Nature 1999402 904-9. 23, Zalse MM, Axmann FR, Zwerina J, ef. Treg cols suppress ‘osteoclast formation. A new ink between the smmune system and bone. Aris ou 2007:6:4104 12 24. Lam J, Takesha S, Barker JE ef al. TNFacinduces osteclastogenesis by dec simulation of macrophages exposed to permissive levels of RANK ligand. J Cin Invest 2000, 106: 1381-8. 25, Salo K, Suematsu A, Okamoto K, ef al Th17 functions as an osteoclastogenc helper T cll eubset that inks T cel action and hone dsinucson. J Exp Mes 2006:208:2673-82. 26. Axemana R, Bohm C, Kronke G, ef a Inhibsion cf ites receprdiecty blocks ostecclas ormaton In vio an in Vuo ‘Année: eu 2009%60:2747-56. 27. Chon XX, Baum W. DnyorD. of a Sclrastin inhibin reverses sjstomic,poraricula and local bone lose in artis. An Acura Des 2013:72:1732-6, ‘riot K eral AMD Open 2016; =000014,do10.11a6/mdopen 2014 000014 :yBLAdoo Kq paroaroie son6 Aq 2Z02 “6 YO!EWN Uo /WU09 Tue: vadopUN)'d)\| WOH paPEOIUMER “sLOZ LudY g UO 71 0000-rL0z-UadopUY/gEL 0} Se paysiIand ysiy ado GW28. Haro U, Goorgess D, Bang Ho Induction of osteocastoganesis, and bona loss by human autoantibodies agains cirulinatod \imentn. J cin ives! 2012:122.1791-002 28. Canalis E, Mazziti G. Gstina A, e a Glucocortcoisinduced osteoporosis pathophysiology and therapy. Osteopors it Boor 8 1319°28, 20, TanFN, Gunawardene SC, Lee H, eta. fects of ow-dose prechisone on bone metabolism. Bone Miner Fes 20052046470. 31. Lane NE, Ya0 Wi, Balooch M, ef al. Gucocoricou-teated mice have localized changes in trabecular bone material properties and ‘osteocyte lneunar size thal ae nol Soserved in placebo rested or fstogon-deticent mice. J Bone Tinos es 2008:27-406-76, 32, Weinsoin RS, Jka RL, Part AM, ef al Inhbvon of ‘stecbasiogenesis and promoton of apoposs of ostocblats and bsteccyee by gucocoricads. Potential mecnarisms af har falters effects an bone Cin inves 1996-1022274-82. 38, Perera RC, Delany AM, Canals E Eflcs of cotsolandbone ‘morphogonatc protin2 an somal al diferantaon: coeation with CCCAAT-onhancer binding posi expression. Bore 2002 30-685-01 34. MoS, Suzuki N, Kalo S, etal Guucocortcolds induce the Sfereniaton ofa mesenchymal progeator cel ine, ROB-C26 ino Aaspocyis and ostgobass, bu fal induce terminal osteoblast Siferoniaton. Bono 2007:4034-62. 35. OBron GA, Jia D. Poin Li, ef Gucocortooiés act dec on osteobiasis and osteooyes fo induce tr apopiosis and reduce bone formation and strength. Endocrinology 2004; 145:1895-81, 86. Ohnaka K, Tanabe M, Kawate H, ef al Giucocoricod suppresses tho canoeical Whit slghalncuturod hun ostenblasts. Blacher ‘Blopnye fs Commun 2005;20077-81 37. Wang FS, Li CL, Chon Yd, eta Secreted tazied-elated protsin 1 ‘modiates glucocoricadestenuaton of osteogenic actives and bong mass: Endocrinogy 2005; 146:2418-28, 38. Lu, Pota A, Pong X, eta. Prevention of gucocortcoisinduced apopiosis in osteacytes and osteoblasts by ealindn-O28k ¥ Bone Iinor Ros 20081 9:479-00. 38, Swanson C, Lorenzon Ml, Conaway HH, eal. Glucocoricod raguaton of enteaclatcferenaten and expraesion of receptor Aactvatr of nuclear factor-kappaB (NFAappab) igen, {steopretegonn, and receptor acbvator of NF-kappa in mouse Calvan bones” Endocrinology 2006, 147.3813-22. 40. Fubn MR, Bezkin JP. Tho roto of parathyroid hormone in the pathogoness of gucsconicad:nduced astaopoross: fre-examinaton ofthe evidence. J Cin Endocr! Metab 2002187. 4053-41 41, Cooper MS, Blumaotn A, Goddard PE, eta. 1 beta hydroxystorkd ‘denpdroganase type T actaty predicts he elects of gucaconcads fon bone, J Cin Brdcrnal Mets 2008898747, 42, Cooper MS, Bujalska | Rabbit E, et al Modulation of 11 botasnydroxistoroid dehydrogenase isozymes by prinlammatony {ines i estpblass an auoerine sith orm glucocorbook Itactvaton to actvaton. J Bone ner Fes 2001;16:1087—44. 43, Russchor H, Smit P, van den Akker ELT, ofa Two polymorphisms In the gucocoricod receptor gene deci atfect (ucocaricodegulated gone expression. J Ci Endocrinol Metab 2008,90:5804-10. 444. van Siaa TP, Leukens H, Cooper C. The epidemiology of Ccontcosterod induced osteoporesis: a metaanalyis. Osteopores Int 2002:13.777-87 45. VanStaa TP, Leutens HG, Abenhaim L, eal Use of ol Coniosterds and eof ectres. ons nar se 2000,15:088-1000, 48. Kanic JA, Johansson H, Od A, eA meta analysis of prior Coroetoroid use and fracture rk J Bons Viner Fes 20041018909 47. Rogol A, Gugiein G, Dove A, eta High prevalence of asymotomate vertebral fractures in postmenopausal women Feoeluing chronic gucocoricold therapy a cross-sacbonal outpatient study. Bone 2006 39:253-9, 48, Van Staa TP Laan Ri, Boron IP, a Bone densty threshold ana ‘ther pects of vertebral fracture in patents eveting orl (ucocotcoid therapy. Aris Aneu 2008;11:3220-0. 49. Majundar SA, Monn SN, LX LM, ef nuance raconcy and duration glcocariccg use on fone mneal dost and ik ol tatu Population-based conor stuty. Osieqpors nt 2013:24 2480-6, 50, Selby PL Haley JP. Adams KRH, etal Cortcosterods donot ater the threshold for vertebral fracture, J Bone lane” Fes 2000; 15:952-6, S51. Brot K, Comet 8. Roux C, otal 2014 updata of commendations fon the prevention and reament of ucacoricaiinaesd bsteoporess. Jan Hone Spine 2014;81:495-501 hrm shal ac id FRAX Lab ES, Saag KG, Adachi JO, of al, FRAX(®) Postion Dovelopment CConterence Members Oficial Positions for FRAX(@) cinical Be 7 6. 6, or. 1. ES 1. regarding glucocorticids: the impacto the use of gucacoticids on the esimale by FRAX() ofthe 10 yor tskot acre tom Joint Ctl Postions Development Conferonce othe intemational ‘Sosety for Cinial Denstomety and inemational Osteoporosis Foundavon on FRAX(@). J Cin Donsiiom 2011.14212-18 (Grossman JM, Gordon F: Ranganath VK, eta. Amenican College of Rheumatology 2010 racommentations forthe provenion ana ‘teatmant of ueccortcatznduced osteoporosis. Ants Care Ras (Movoker) 2010:62:1515~26, [Lokamwasam S, Adachi JD, AgnusdoiD, ota Joint OF-ECTS GIO Guidelines Working Group. A ramework for the development of {uideines for he management of glucocorbcod induced Osteoporosis, Osoopoves Int 2012.28:2057-76, Wibandis CA, Kisasen Ri Dikgraal MGW, 8 a Bone mineral density in eumatod ans patents | year afer adalimumab ‘therapy: arrest of bone loss. Ann Feu Dis 2000;68:373-6 Haugeberg G, Conaghan PG, Quinn M, etal Bone oss in patents ‘with acve oalythoumatod arth infiximab and methotorato Compared with metherexte eaten! alone. Explore analyse trom a f2momth randomised, double bing, placebo-contraled sity. ‘ann houm Dis 200038: 1698-20" HaugebergG, Stand A, Kvion TK etal Reduced los of hand bone dost wih prechisolone in ary houmatoid aris: resus rm 2 randomized placabo contol al. Ac Into Med 2005; 165:1295-7, {Ger-VokselM, Bjsterboscn J, Goekoop-Ruterman YP, et at Changes in bone mineral density in patents wih recent onset factve meumatd artis, Ann Foun Dis 2008 67 823-8. Kanal VK, Grjava CG, Arbogast PG, ta Intaton of tumor neeross factor « aniagoniss and risk af ractures i patients with Selected rheumatic and autoimmune diseases, Arnis Care Fs 2013 85108894 Ghazi Mi, Kota, Brit K, ef a Prevalence of vertebral facture in patons wih eumatod artis: revsting the role of ‘ucocotaids, Ostaqpors nt 2012:28.81~7. Bussey Ui, Lo ES, Cartlaro KS, etal Calum and vain 03 supplementation prevonts bone loss inthe spa secondary 10 lonedose cortcosierads in patients with theumatod ants. ‘nn Intern Mod 1906;125:901-8. ‘Adachi J, Bancen WG, Blanc F, ta. Vitamin D and calcium inthe provenion of coicostroidinducod ostooporsi: a year alow, {J Rheumatol 199623 995-1000. Saag KG, Emkey R, Schnitzer TY, etal. Alendronate forthe prevention and treatment of glucocartcadsnduced osteoporosis Weng! J hed 1960330 292-9, ‘Adgen JD, Saag KG, Deimas PD, otal Two-year etocts of alendronate on Bone mineral density and verobral return patents ecening glucocoricods: a randomzed, double-bind placebo controled extension tal, Advis Roum 200144 boost? Cohen 8, Levy RM, Keller M, et al. Fiseoronate therapy prevents comieastrodduced bone loss: a weve month, maltooner, Fandomized, double-blind, placebo-contled, parale-group study. ‘Ants neu 1900:42:2800- 18. Feld OM. Hughes FA, Laan AF et a Etfcacy and safety of day rseoronaie inthe teaiment of contcosterogsndiced osteoporosis men and women: avandomized tal Euopean Conicostorod induced Osteoporosis Treatment Study. J Bone Miner ‘as 2000;15:1008-13. Wallach 8, Cohen 5, etd OM, tal Etfects of sedrenate treatment ‘on bone dans and verbal ractura in pabents on coricosterod Thorapy. Cal Tissue int 2000:67.277-85, eid DM, Devogolar JP, Saag ka a Zoledone ac and Fsedronat nthe prevention and eatment of glucocoricldinaced ‘steoporsis (HORIZON): a mulicente,double-bind,doubl-durmy, Fangomssed contd Wal. Lance’ 2008°373-1255-83, Barasen A, Cunha-Cruz J, Curo FA of al Pik factors for stecnecrose ofthe laws: a case-cotel stay rom te CONDOR dental BRAN, J Dent ies 2011 00:400-44 Feldstin AC, Black O, Pern N, etal Inedence and demography of fomur tacturés wih and witout atypical features. J Boro Minor Bos 2012.27 977-06, ‘Thomas T, Hoa S, Ringe JD, etal Oral bisphosphonates reduce the rsk of circa Fractures in gucocortcoidsnduced ostoopoosi inca practice, Osieoporos In 201824 263-9. (veman RA, Gouray ML, Deal CL, at al Fracture rate associated ‘wth qualty mete-bated ant-osteoporsi reiment (ucocoricadtanduced osteoporess. Osteoporos Int 2015 Jan 20, [Epub ahoad of pret, ‘Majumdar SR, Ux LM, Morn SN, et The dsconnect botwoon boter quay of gucocorbcolas:induced esteoporess prowentve ‘Brot K etal AMD Open 201512000014, do 10.1136/imdopen-207¢-o00074 UBUAdoo Aq paypajoid SaNb Aq ZZOz “6 YoLEWN UO /WU09 Tuue-UadopUN)-djYy WOH PAPEOIUMER “SLOz LUdY UO »L0000-r102-UadoPUM/gE 04 S PAYSIANd iy :UadO GWA7, care and better outcomes: a population based cohort study. ‘TBhoumatol201340"1736-41 Dore Ak, Cohen SB, Lane NE, o al, on behalf of he Denosumad FRA Study Group, Etects of enosumab one bane mineral density and bone turover inpatients wth rheumatoid arts recetvng ‘concurrent gucacoricads or bisphosphonates. Ann Rheum Dis 2orwsea7e-s. thirty-six month results ofa randomized, double-blind, controled Wal Ante hour 2000;60'3346-58. 78, National osteepore3 foundations lnican’s guide 10 the prevention and treatment of osteopoross, Washington DC: National steopoross Foundation, 2008, 79, Bone and Tooth Socety of Great Britain, Guidelines onthe iproventon and treatment of ucacorteais induced osteoporosis 76. Saag\KG, Shane E, Boonen S, etal TeHparate or alendronate in London: Royale College of Physicians, 2008. (Gucocaricod:nduced orteoporste. Eng Wed 2007-987 2028-39, 0, Rlzzal'A. Adach JD, Cooper . ea Management ot 7. Saag XG, Zanchota JA, Dovogolaar JP Elects of tiparabde glucocoticodtinducsd osteoporosis. Cal issu Int ‘versus alendronate for eating lucocoricac-induced ostecpoross: 2o12.91225-43, a ‘Brot K, eral AMD Open 2016;1 2000014. do:10.1136/mdopen-2014-000014 YBAdoo Aq parpayoig sanb Aq zz0z “6 YoEWN UO /Wu09 Tusa vadopuLH)'dyy WON papEo|UMEG "sLOz Udy g UO »/.0000-r10z-UadopUH/ge! 0} Se PaYsiIand sil :YadO GN