Glucocorticoid Associated Osteoporosis 1950 Raoul Dufy - PowerPoint PPT Presentation

The Many Benefits of Glucocorticoids Glucocorticoid Associated Osteoporosis 1950 Raoul Dufy Prevention and Treatment Tomorrow I sail to Boston in search/Of my Jonathan Graf, MD hands. . . . Fifteen years ago the attacks began. Disfiguring my Professor of Clinical Medicine UCSF hands/As if I were painting with leaden Division of Rheumatology, San Francisco General gloves. . . . My only wish: to draw Hospital freehand/Following the wind/ 1951 ”La Cortisone” Flowers that beckon me/And capturing them/In a vase of Anemones. Question #1 And the drawbacks…. Bone loss in GIO is bimodal and occurs rapidly in an early phase (weeks) and more gradually in a later phase. Which one of the following primarily occurs in 1952 the early/rapid phase? 56% A. Increased osteoblast apoptosis (cell death) B. Increased osteoclast activity 1951-1953 Dufy finished over 200 18% 15% C. Decreased osteoblast activation 10% paintings. But he passed away due D. Combination of A,B,C to a GI hemorrhage at least partially Combination of A,B,C Increased osteoclast activity Decreased osteoblast act... Increased osteoblast apo... caused by his therapy 1

Steroids Fracture risk Glucocorticoids: Some toxicities increases with AGE, GENDER, Diabetes and Dose HIGH Cataracts Van Staa et al, JBMR, 1998 HTN MEDIUM Weight gain Fluid retention PUD WOMEN Myopathy MEN Psychiatric OSTEOPOROSIS & OSTEONECROSIS CONTROL 50% of patients * GLUCOCORTICOIDS: “ Double Glucocorticoid Effects of Bone Whammy to Bones ” Weinstein R. NEJM 2011;365:62-70 Increased apoptosis of osteocytes (bone quality Biophasic effect: Osteoclast effects are early and osteoblast are late decreased before BMD) Osteoclast /Pro-resorptive effects (early) Prolonged osteoclast survival and decreased – Decrease OPG osteoclastogenesis – Increase RANK-L   osteoclast #, Increased Osteoclast bone activity, lifespan resporption Anti bone-formation effects (late) Decreased Decrease osteoblast and osteoclast formation osteoblastogenesis and increased apoptosis Decrease osteoblast lifespan Enhance apoptosis in osteocytes Multiple pathways affected!!!! Increased bone resportion relative to decreased bone formation and decreased overall bone quality: 2

GLUCOCORTICOID - INDUCED Glucocorticoid Effects on Remodeling/Strength OSTEOPOROSIS  Early phase of rapid bone loss (Pro-resorption) – As early as 2 mos into therapy  – Resorption markers elevated – Pts on high dose prednisone can lose 15-20% of trabecular bone (spine) in 5-7 mos X many… Slower phase of bone loss (Anti-Formation) – Continues indefinitely – Trabecular bone especially vulnerable Manolagas, JBMR , 2000 Relative Rate (  95% CI) of Non-vertebral Fractures : D/C Steroids Question #2 (5 years) - REVERSAL What is the minimum dose of daily prednisone associated with a significant increase in hip fracture risk? (Ave. dose for acute COPD flare 50-60 mg/day) RR 49% A. <2.5 mg  40% B. 2.5-5mg C. 7.5mg-12.5 mg D. >12.5 mg 7% 4% g g g g m m m m  5 5 5 5 - 2 . 5 2 . 2 . . < 2 1 1 - > g m 5 . 7 3

SUMMARY Relatively low doses of po GCs (2.5-7.5 mg Pred) increase fracture risk Increase in risk is quick -- within 3 mos of starting therapy Vulnerable population: postmenopausal women, elderly pts Fracture risk decreases if stop therapy More falls in steroid-treated patients (more frailty, less mobility, less activity) van Staa et al, JBMR , 2000 Summary of professional organization guildelines 2017 American College of Weinstein R. NEJM 2011;365:62-70 Rheumatology Guidelines on GIOP Systematic literature review summarizes evidence for risks/benefit of GIOP prevention and treatment using G.R.A.D.E. methodology 1) Risk Assessment 2) treatment and 3) follow up – Adults – Women of childbearing potential – Adults requiring very high doses of glucocorticoids – Adults with organ transplants – Children ages 4-17 4

GIO, fracture risk, & effect of other factors: Principles Reflected in ACR 2017 guidelines Glucocorticoids are not given in a vacuum Calcium and Vit D usage deemed low enough risk that recommended for all. GIO does not occur in vacuum but involves other OP risk factors Guided by risk/benefit assessment: risk assessed using FRAX + adjustment for pred dose > 7.5 mg/day (1.15X FRAX for major OP fx, 1.2X FRAX for hip fracture) Risk calculators stratifying GC use as low/high (<>7.5 mg/day) underestimate risk associated with higher daily GC doses Observational data suggest risk to young women and children receiving high dose GC’s Weinstein R. NEJM 2011;365:62-70 I. Clinical fracture risk Initial risk assessment workflow assessment Risk assessment should be undertaken within 6 months of starting therapy Periodic reassessment of risk: – Every 1-3 years for adults not on therapy – 2-3 years (BMD) for high risk adults (> 40 yrs) on therapy, adults who’ve completed OP treatment, and higher risk younger adults 5

Strategy for reassessment Assessment of 10 Year Fracture Risk Low Medium High <10% 10-20% >20% ACR 2017 Guidelines definition of risk: II. Treatment: Moderate/high risk Recommendations are conditional for Women not of childbearing potential and men: moderate risk & strong for high risk (order of preference) 1.Oral bisphosphonate 2.IV bisphosphonate 3.Teriparatide 4.Denosumab 5.Raloxifene (PMP women as last resort) 6

Treatment: High dose GCs Treatment: Moderate/high risk Adults > 30 years Women of childbearing potential (conditional): (order of preference) Initial prednisone dose > 30 mg/day or cumulative dose > 5 grams in 1 year 1.Oral bisphosphonate 2.Teriparatide 1.Oral bisphosphonate 2.IV bisphosphonate 3.IV bisphosphonate (high risk only) 3.Teriparatide 4.Denosumab (high risk only) 4.Denosumab 5.Raloxifene (PMP women as last resort) Question #3 III: Follow up True or False: After 5 years of treatment: There have been no head to head – Continue therapy if still assessed at mod/high comparative effectiveness studies of risk. bisphosphonates for GIO: 67% A. True After discontinuing GC treatment B. False – Mod/high risk: continue treatment 33% – Low risk: discontinue treatment What about therapeutic “failures?” e e u s r a l T F 7

What about Zoledronic Acid? Better than other Horizon Results: 12 months bisphosphonates?: Horizon Reid et al. Lancet. 2009 Apr 11;373(9671):1253-63 1 year randomized double blind, double dummy, non-inferiority 833 patients – Subdivided into treatment groups based on duration of steroid therapy (>< 3 months) IV ZA 5mg vs. PO Risedronate 5mg Primary endpoint: BMD LS spine Figure 2. Change in mean bone mineral density of lumbar spine and femoral neck for (A) treatment and (B) prevention subgroups Error bars=95% CI. *p=0·0005. †p=0·0001. ‡p=0·0050. § p<0·0001. ¶p=0·0156. p=0·0049. PTH vs. bisphosponates: PTH vs. alendronate: 18 month Beneficial for GIO? (2008) interim analysis Saag et al. NEJM 2007;357:2028-39 36 Month randomized double blinded controlled 18 month interim analysis 428 patients studied – Treated with GC ’ s for at least three months – Prednisone equivalent of 5 mg/day or more More than 25% attrition rate in both arms – 20 mcg/d PTH vs. 10 mg/d alendronate 8

PTH vs. alendronate: 36 month PTH vs. alendronate: Fracture fracture follow up Results: 18 month analysis Saag et al. Arthritis Rheum. 2009 Nov;60(11):3346-55 At 36 months, statistically significant reduction in both radiographic and clinical vertebral fractures No significant differences in non- vertebral fractures Den v. Ris: bone turnover results • 795 men and women • Taking or starting GCs >7.5 • Not a FX prevention trial mg/day • Denosumab has rapid off-action • Required hx of OP fx or • Follow with another agent BMD<2 • May 2018 FDA approval • Primary endpoint: non- inferiority change BMD spine • Denosumab met primary endpoint at 12 months 9

Follow Up Treatment: Thank You! Treatment “failures” For adults > 40: – Fracture > 18 months on treatment – Loss of BMD> 10% year Teriparatide or denosumab IV bisphosphonate if failure thought due to non-compliance or oral absorption Horizon Demographics: A Extra Slides representative population Majority of patients were on more than 7.5mg prednisone a day! Majority of patients had rheumatoid arthritis or SLE Higher risk patients studied – in order to maximize potential effect size 10

PTH vs. bisphosponates: Who were the Patients? Beneficial for GIO? (2008) Saag et al. NEJM 2007;357:2028-39 BMD<-2.0 or <1.0 + fragility fracture (Higher risk patients) 36 Month randomized Exclusions: Standard for PTH Use double blinded controlled Two treatment groups similar (n=214 both) 18 month interim analysis 428 patients studied Alendronate PTH – 22-89 years of age Age 57.3 56.1 – Treated with GC ’ s for at least three months Prednisone dose 7.8 7.5 – Prednisone equivalent of 5 Non Vert Frag Fx 20.1% 19.6% mg/day or more BMD T score LS Spine -2.6 -2.5 – 20 mcg/d PTH vs. 10 mg/d alendronate BMD T score Hip -1.9 -2.0 – Everyone continued Ca/VitD Patients ’ Underlying Disease PTH vs. Alendronate More than 25% attrition rate in both arms High risk for fx: higher prednisone dose, lower BMD, and RA/SLE diagnosis 11

PTH vs. alendronate 36 month Follow Up: BMD results Saag et al. Arthritis Rheum. 2009 Nov;60(11):3346-55 PTH PTH PTH 12