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Steroid-induced osteoporosis: screening and treatment strategies

Steroid-induced osteoporosis: screening and treatment strategies. BY Walaa F. Elbaz MD Professor Internal Medicine, Rheumatology & Immunology Alazher Universty (girls). Glucocorticoids.

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Steroid-induced osteoporosis: screening and treatment strategies

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  1. Steroid-induced osteoporosis: screening and treatment strategies BY Walaa F. Elbaz MD Professor Internal Medicine, Rheumatology & Immunology AlazherUniversty (girls)

  2. Glucocorticoids • GIOP is the most common cause of 2ry osteoporosis, 1est cause ˂ 50 ys ,1 iatrogenic cause of it. • GC are used for inflammatory rheumatic disorders (RA, PMR…) and lung disorders (asthma and COPD), dermatological, malignancies and solid organ transplants. • Prior and current exposure to GCs ↑ the risk of fracture, bone loss; highest risk with postmenopausal(PMP) ♀and older ♂. • Underlying inflammation also has a role in bone fragility rapid bone loss at the initiation of GCs. • FardetL,etal.: Medicine (Baltimore) 2015;94:e647.

  3. The prevalence of use of oral GCs in population is between 0.5 and 0.9% (1% in US) (65% ♀), rising to 2.7% in ♀ aged ≥50 years. • 10% of patients with long-term GC treatment  diagnosed with a fracture, 30–40% have radiographic vertebral fractures. • The highest rate of bone loss occurs within the first 3–6 months and a slower decline with persistent use at low doses prednisone 3–10 mg. • Roux C: OsteoporosInt, 2011;22:421–33. • Overman RA, etal.: Care Res 2013;65:294–8.

  4. Both high daily and high cumulative GC doses ↑risk of fracture, particularly VF due to greater effects of GCs on trabecular bone > cortical bone. • GC treatment is a potentially reversible risk factor for GIOP; • Despite increasing information about risk factors for fracture and the presence of effective therapies, many long-term GC users never receive therapy to prevent bone loss or fracture. • Recently There are greater awareness of GIOP, with ↑ number of patients receiving ttt. • Duyvendak M, et al.: Osteoporos Int 2007;18:1429–33.

  5. Major risk factors that cannot be changed: • Older age (children are at risk too) • Non-Hispanic white or Asian ethnic background • Small bone structure • FH of osteoporosis or an osteoporosis -related fracture in a parent or sibling. • Prior fracture due to a low-level injury, particularly after age 50 • LeBlanc CM, et al.: J Bone Miner Res 2015;30:1667–75.

  6. Risk factors that may be changed: • Low levels of sex hormone, mainly estrogen in♀ (menopause) and ♂ • The eating disorder anorexia nervosa • Cigarette smoking, Alcohol abuse • Low CA and vit D, by low dietary intake or poor absorption. • Sedentary (inactive) lifestyle or immobility • Certain medications besides GC, including the following: • Excess thyroid hormone replacement, heparin • Some treatments of breast cancer (Arimidex, Femara, etc.) or prostate cancer (e.g., Lupron) that deplete sex hormones • A disease that can affect bones • Endocrine diseases (hyperthyroidism, hyperparathyroidism, Cushing's • Inflammatory arthritis (RA, AS, etc.) • Feldstein AC,et al.:OsteoporosInt 2005;16:2168–74.

  7. Pathogenesis Role of underlying inflammation • In the general population, small ↑ of CRP within the normal range ↑ non-traumatic fracture risk and ↑ inflammatory markers and cytokines are prognostic for fractures. • RA doubles the risk of hip and VF, regardless use of GCs,and disease activity is consistently associated with low BMD. • A prospective study of early RA patients  high bone loss was observed mainly with persistent inflammation ( persistent ↑↑CRP). • In AS, inflammatory disease, GCs are not used, there is bone loss and an ↑ risk of vertebral fractures, driven by inflammat • Schett G, et al .:Arch Intern Med 2006;166:2495–501. • Briot K, et al.: Ann RheumDis 2013;72:1914–19.

  8. The mechanisms for these clinical observations: • Osteoclastogenesis is under the control of RANK-L produced by osteocytes in normal bone remodelling, but also by lymphocytes and fibroblasts in others; oestrogen deficiency and inflammation. • Osteoclastogenesis can be enhanced by cytokines, driven by Th 17 ( IL 6 and IL23). • TNF-α transgenic mice are models of osteoporosis with dramatic ↓ in bone mass and deterioration of bone microarchitecture. • Moreover, an over expression of sclerostin has been observed in these models, with a consequence of inflammation-related decrease in bone formation. • Autoimmunity has a role in bone remodelling, as antibodies; ACPAs can ↑osteoclast numbers and activity through citrullinatedvimentin located at the surface of precursors (a TNF-α local effect).inflammation has a deleterious effect on bone remodelling, inducing an ↑in resorption and a ↓in formation, before any effect of GCs. • Zaiss MM, et al.. Arthritis Rheum 2007;56:4104–12. • Chen XX, et al.: Ann Rheum Dis 2013;72:1732–6.

  9. Bone effects of GCs A direct negative effect of GCs on bone cells, a reduced rate of forming new bone. • Prednisone 5 mg daily is enough to rapidly & significantly ↓serum P1NP and osteocalcin, (markers of bone formation). • GCs at high concentrations dramatically ↓ osteoblast and osteocyte numbers and activity. • Reduce the recuitment of osteoblast precursors ↓ Osteoblast differentiation by induction of adipogenetic transcription factors (PPARγ) and suppression of Wnt protein signalling. • ↑ osteoblast and osteocyte apoptosis is associated with caspase 3 activation. • Osteoblast function is ↓ through the antianabolic effects of GCs, such as ↓ GH, IGF1 and IGFBP ↓ IGF2, another local regulator of osteoblast function. • Ito S,, et al.: Bone 2007;40:84–92. • O’Brien CA, et al.: Endocrinology 2004;145:1835–41. • Ohnaka K, et al.: BiochemBiophys Res Commun 2005;329:177–81.

  10. GCs ↓ in osteocyte viability, through changes in matrix properties surrounding the osteocyte lacunae. • GC induces prolonged survival of osteoclasts allowing excessive bone resorption primarily in the trabecular bone of the spine. • ↑ the expression of RANK-L and ↓ the expression of osteoprotegerin in stromal and osteoblastic cells ↑ prolonged lifespan of osteoclast, ↓in the lifespan of osteoblasts ↑ • These effects persists throughout GC administration. • Importantly, ↑ fracture risk even before declines in BMD appear, and occur at higher BMD than PMP osteoporosis. • Swanson C, et al.: Endocrinology 2006;147:3613–22.

  11. Indirect effects of GCs • GC↓ GIT absorption of calcium and ↑ renal calcium loss. • 2ry hyperparathyroidism has been suggested as a bone effects. Actually, there is no evidence for elevated endogenous levels of PTH in these patients and histological 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;  one of the determinants of the risk of falls and fractures in these patients. • Canalis E, et al.:OsteoporosInt 2007;18:1319–28. • Rubin MR, Bilezikian JP.: J ClinEndocrinol Metab2002;87:4033–41.

  12. Pathophysiology of glucocorticoid-induced osteoporosis

  13. Differential sensitivity to GCs • There is great variability of side effects of GCs, including bone loss, for unknown reasons may be: • 11β-hydroxysteroid dehydrogenase (11β-HSD) system is a prereceptor modulator, regulator of the effects of GCs on bone. • Catalyses the interconversion of active/inactive cortisone, amplifies GC signalling in osteoblasts. • β11-HSD is widely expressed in GC target tissues including bone, can be modulated and amplified by proinflammatory cytokines, age and GC administration • Individual GC sensitivity can also be regulated by polymorphisms in the GC receptor gene. • Cooper MS, et al.: J ClinEndocrinolMetab 2003;88:3874–7. • Russcher H, et al.:JClinEndocrinol Metab2005;90:5804–10.

  14. Epidemiology • The risk of fractures is ↑ by twofold in with GCs, and risk of vertebral fractures is higher. • Risk of hip fracture is 1.6, and vertebral fracture is 2.6; • The global prevalence of fractures in patients receiving long-term GCs is 30–50%. • Prevalence of vertebral fractures was 37%, with 14% of patients having 2 or more asymptomatic VF. • The prevalence ↑ with age; 48% of patients aged ≥70 years and 30% of those aged <60 years had at least one VF. • Majumdar SR, et al.: OsteoporosInt 2013;24:2493–8.

  15. Epidemiological studies could help to identify a high-risk group of patients. Time effectFracture risk is↑ immediate, as early as 3-6 months after starting therapy and reverses after discontinuation. • This not explained by BMD changes, but related to 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 . • LeBlanc CM, et al. J Bone Miner Res 2015;30:1667–75.

  16. Dose effect • clinical trials and epidemiologic studies Most stratify GC use into 2 categories: low prednisone ≤7.5 mg/day) or high (>7.5 mg/day) (15,16) • Prednisone, 2.5–5 mg/day ↑risk of fractures. • There is a dose-dependent in ↑ fracture incidence. • Doses over 7.5 mg of prednisone have a 5 -fold higher risk of spine and hip fractures. Prednisone 10 mg daily for > 90 days leads to a 17-fold ↑ in vertebral fractures & a 7-fold ↑ in hip fractures

  17. Prior versus current GCs use:Ever use of GCs is associated with an i ↑ risk of osteoporosis and fracture risk in all patients. However, the risk is mainly associated with recent and prolonged GC use > remote or short courses. • BMD loss • BMD loss is an immediate consequence and affects the trabecular bone >cortical bone. • A meta-analysis of sectional, longitudinal studies, bone loss assessed by DEXA  5–15% during the 1est year of treatment. • The main determinant of BMD at any time is the cumulative dose. • The ↑ rate of bone loss persists in chronic GC users, more slowly. • van StaaTP,et al.:. Osteoporos Int2002;13:777–87. • Majumdar SR et al.: OsteoporosInt 2013;24:2493–8.

  18. Assessment of fracture risk Role of BMD • A mismatch between BMD and fracture due to change of bone quality. • Measurement of BMD has limited predictive value in GIOP. • PMP ♀ taking GCs have higher fracture risk than those not using GCs at similar levels of BMD. • There is a debate on T score threshold to intiate treatment in GIOP. • T≤−2.5 as in PMP ♀ is considered ,but a higher level T≤−1.5 is indicated for intervention, ( bone loss can be ≥ 10%). • Despite these limitations, BMD measurement is recommend in the guidelines at the initiation of treatment. BUT, a more assesment of the risk & clinical judgement is needed. • Van StaaTP,et al.: J Bone MinerRes 2003;18:913–8. • Briot K, et al.:. Joint Bone Spine 2014;81:493–501.

  19. Role of FRAX • The WHO fracture risk assessment tool (FRAX) algorithm has been developed to estimate the 10-year risk of hip and major fractures (spine, humerus or wrist fracture) based on clinical risk factors, with or without BMD.  • FRAX risk factors: age, sex, BMI, P. history of fracture, FH of hip fracture, current smoking, alcohol intake, GC use, RA, other causes of 2ry osteoporosis and femoral neck BMD. • These risk factors are largely independent of BMD  thus improve the fracture risk assessment. • Treatment can be considered (without FRAX assessmen) if patients are at high risk if : prevalent fracture, age ≥ 70y , exposure to GC dose ≥7.5 mg / low BMD (T≤−2.5). • Kanis JA, et al.:OsteoporosInt 2011;22:809–16.

  20. limitations of FRAX : • Use of oral GCs is a risk factor but not consider dose, duration. • There is no difference in risk between prior and current use.  • FRAX assumes an average dose of prednisolone (2.5–7.5 mg/day/ its equivalent) so may underestimate fracture risk in higher doses and may overestimate risk in lower doses. • Its predictive value is mainly validated for non-vertebral fractures while principal risk in GCs users is vertebral fracture. • t FRAX is adjusted for GC doses: a factor of 0.8 for low-dose exposure and 1.15 for high-dose exposure for major fractures, and 0.65 and 1.20 for hip fracture probability. • FRAX cannot be used in premenopausal ♀, ♂ aged <40 years and in subjects treated with antiosteoporotic drugs. • Leib ES,, et al., J ClinDensitom 2011;14:212–19.

  21. Role of underlying disease • Persistent inflammation is associated with bone loss as in active RA or SpA patients. • Prospective open studies showed that complete control of inflammation with increased mobility  absence of bone loss . BeSt study, recent-onset active RA patients limited bone loss was in all treated groups, including group initially treated with high-dose prednisone . • However, no evidence for a reduction in fracture risk with controlling this inflammation  needs new studies are (60 • Wijbrandts CA, et al.: Ann Rheum Dis 2009;68:373–6.

  22. Role of patient characteristics • Age, female gender, low BMI, history of falls and previous fractures, duration of menopause and smoking are associated with fracture risk in patients with GCs, similarly to primary osteoporosis. • These risk factors must be assessed in all patients, and all causes of secondary osteoporosis are added risk factors of fractures in patients with GCs.

  23. Initial fracture risk assessment.

  24. Fracture risk categories in GC-treated patients High fracture risk Adults ≥40 years of age • Prior osteoporotic fracture(s) • Hip or spine BMD T score ≤ -2.5 in men ≥ 50 years and PMP ♀ • FRAX (GC-adjusted) 10-y risk of major osteoporotic fracture ≥ 20% • FRAX (GC-adjusted) 10-y risk of hip fracture ≥ 3% Adults ˂40 years of age • Prior osteoporotic fracture(s) Moderate fracture risk Adults ≥40 years of age • FRAX (GC-adjusted) 10-y risk of major osteoporotic fracture 10–19% • FRAX* (GC-adjusted) 10-y risk of hip fracture >1% ˂3%. Adults ˂40 years of age • Hip or spine BMD Z score <-3 or • rapid bone loss (≥10% at hip or spine over 1y) • And continuing GC ttt ≥7.5 mg/day for ≥ 6 months

  25. Low fracture risk • Adults ≥40 years of age • FRAX (GC-adjusted) 10-y risk of major osteoporotic fracture >10% • FRAX* (GC-adjusted) 10-y risk of hip fracture <1% • Adults ˂40 years of age • None of above risk factors other than GC treatment. • KanisJA,et al.:OsteoporosInt 2011;22:809–16.

  26. How is GIOP treated? General measures • Patient's height must be measured initially, as height loss later could be due to asymptomatic vertebral fractures. • No indication for assessment of biochemical markers of bone remodelling at the start, during follow-up, as bone turnover is consistently low in GC users. • Daily dose of GCs must be constantly as minimal as possible, alternatively IA injections may be used. • The risk of falling should be assessed: In elderly patients, painful joints of LL and massive doses of GCs. • Encourage physical activity.

  27. All guidelines, ACR, IOF, and the Belgian Bone Club (BBC) recommend CA (1000–1500 mg/day) and vit D (800 and 2000 IU/ day )should be used, although controversies about their effect on BMD (?? +ve effect spine).   • If vit D is low need more vitamin D supplementation • Start medications will depend on other risk factors,, as well as BMD results by DEXA.  • National osteoporosis foundation’s clinician’s guide : National Osteoporosis Foundation, 2009. • Rizzoli R, et al.: Calcif Tissue Int2012;91:225–43.

  28. Pharmacological treatment Bisphosphonates and teriparatide: • FDA approved Bisphosphonates as the standard care for prevention and treatment of GC-induced bone loss. • Efficacy on fractures is mainly based on the short-term, long-term changes in BMD, reduction of fracture risk in patients PMP osteoporosis. • They are the more popular antiosteoporotic drugs. Alendronate, and zoledronate prevent bone loss at the spine and hip in patients with GCs for ≥ 4 months. • A reduction of fractures in the first year of therapy:  • Reid DM, et al.:. J Bone Miner Res 2000;15:1006–13. • Reid DM, et al.:. Lancet 2009;373:1253–63.-;.km dcz1

  29. Zoledronic acid induced a higher BMD >risedronate (+4.06 vs +2.71%) and higher prevention (+2.6 vs 0.6%) of fracture risk over 1 year at the lumbar spine. • Well-designed studies  the efficacy of bisphosphonates in reducing fractures (48%), a better efficacy when used within 90 days of chronic GC use. • Other studies not support these conclusions, there is still a disconnect between GIOP care and improvement of outcomes. • Thomas T, et al.: Osteoporos Int 2013;24:263–9. • Majumdar SR, et al.: J Rheumatol 2013;40:1736–41.

  30. osteonecrosis of the jaw and atypical femoral fractures are very rareside effect of long-term administration of antiresorptive. • Buccal hygiene should be considered to prevent any local↑ risk of infection. ?? these rare events can change the duration of treatments in long-term GC users. • Bisphosphonates should be used cautiously in premenopausal women, as they cross the placenta; if necessary appropriate contraception ,and give a short bone half-life bisphosphonate. • Feldstein AC, et al.: J Bone Miner Res2012;27:977–86.

  31. Teriparatide • For patients intolerant of Bisphosphonates teriparatide is an alternative,↑ spinal BMD faster and to a greater > it and ↓ vertebral fractures (0.6% versus 6.1%, p = 0.004) • The anabolic effect of teriparatide counteract the deleterious effects of GCs and prevents osteoblast and osteocyte apoptosis resulting in reduced fracture risk. • teriparatide 20 µg daily  ↓A significantly number of vertebral fractures was than antiresorptives. • Saag KG, et al.:. N Engl J Med 2007;357:2028–39. • SaagKG,et al.:. Arthritis Rheum 2009;60:3346–55.

  32. Denosumab • T inactivates the body’s bone breakdown mechanism. • It is the first biologic therapy approved for osteoporosis treatment. • It (prolia) targets RANK Ligand • ↑BMD similarly in patients with and without GCs. • Denosumab is used in patients with contraindications for bisphosphonates, such as renal insufficiency. • It improves the BMD RA patients receiving oral GCs. • Dore RK, et al.:. Ann Rheum Dis2010;69:872–5. • Silvermann S, et al.:OsteoporosInt 2015;26:419–20.

  33. Initial pharmacologic treatment • Adults: Women ≥40 ys of age, not of childbearing potential and men ≥ 40 ys of age; who are at moderate-to-high risk of fracture  treated with oral bisphosphonate (strong). • IF oral bisphosphonates are not appropriate ( due to comorbidities, patient preference, no adherence with an oral medication regimen), IV bisphosphonates should be used > calcium and vitamin D. • If bisphosphonate treatment is not appropriate, teriparatide should be used > calcium and vitamin D. • If none of these treatment is appropriate, denosumab should be used > calcium and vitamin D. • For PMP women if none of these medications is appropriate, raloxifene should be used >calcium and vitamin D. • The order of the preferred treatments was based on a efficacy (fracture reduction), toxicity, and cost.( conditional)

  34. Adults ˂40 ys of age: (women not of childbearing potential and men) with  oral bisphosphonate should be used rather > CA and vit D. • If oral bisphosphonate is not appropriate, same medications listed for adults ≥ 40 ys of age • Raloxifene, is not used in men and premenopausal♀. These conditional recommendations.

  35. Initial pharmacologic treatment for adults.

  36. Special populations. • ♀ with moderate-to-high risk of fracture and of childbearing potential, not plan for pregnancy  use an oral bisphosphonate >ca, vit D. • If oral bisphosphonate is not appropriate, use teriparatide >ca, vit D. • If both are not appropriate, denosumab, IV bisphosphonates  used only in ♀ at high risk of fracture due to associated potential fetal harm. • If an oral bisphosphonate and teriparatide is not appropriate. Denosumab or IV bisphosphonate  initiated only after telling patient about potential fetal harms with unplanned pregnancy. conditional . • There is a lack of data on the safety of currently OP treatments during pregnancy no ttt other than CA, vit D and lifestyle modification. • Stathopoulos IP,, et al.: Hormones (Athens) 2011;10:280–91. • Green SB, Pappas AL.: Am J Health Syst Pharm 2014;71:2029–36.

  37. adults ≥ 30 years of age who are receiving very high-dose GC (prednisone dose ≥30 mg/day /equivalent] and a cumulative annual dose of .5 gm)  oral bisphosphonate • If it is not appropriate, the age-related recommendations for second-line therapy (≤40, >40 ys)  followed (with adjustments for ♀of childbearing potential. Conditional • adults who received an organ transplant and continuing GCs ttt same guidelines for ♂ and ♀, with no transplants if GFR ≥30 ml/minute and no evidence of metabolic bone disease. (54) • NO use denosumab because of lack of safety data in patients with multiple immunosuppressive agents. conditional.

  38. GC-treated children 4–17 years of age, CA intake of 1,000 mg/day and vit D intake of 600 IU/day is recommended. • Children with OP fracture, continue GC treatment at a dose of ≥ 0.1 mg/kg/day for ≥ 3 months, treatment with an oral bisphosphonate / IV bisphosphonate if oral treatment is not appropriate) is recommended conditional

  39. Recommendations for follow-up treatment for prevention of GIOP* • Adults age ≥40 ys continuing GC treatment, a fracture occurred after ≥18 months of treatment with oral bisphosphonate / had a significant loss of BMD (≥10%/y) • Treat with another class (teriparatide or denosumab; or, IV bisphosphonate with CA and vit D Conditional • Adults age ≥ 40 ys who completed 5 years of oral bisphosphonate and continue GC treatment and at moderate-to-high risk of fracture continue active treatment ( oral bisphosphonate or IV bisphosphonate / switch to another class)..Conditional • Adults age ≥40 ys taking an OP medication + calcium and vitamin D  discontinue GC and at low risk of fracture discontinue the OP medication but continue CA, vit D. • Adults age ≥ 40 yrs taking an OP medication, calcium and vitamin D  discontinue GC and at moderate-to-high risk of fracture complete OP treatment

  40. Reassessment of fracture risk.

  41. 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 treat-to-target strategy focusing on low disease activity is effective on bone loss. New epidemiological data are needed to assess the benefit of such a strategy on fracture incidence.

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