Traditional rheumatology practice Glucocorticoid Associated Osteoporosis Prevention and Treatment Jonathan Graf, MD Professor of Clinical Medicine UCSF Division of Rheumatology, San Francisco General Hospital Question #1 Question #2 Bone loss in GIO is bimodal and occurs rapidly What is the minimum dose of daily in an early phase (weeks) and more gradually in prednisone associated with a a later phase. Which one of the following significant increase in fracture risk? primarily occurs in the early/rapid phase? (Ave. dose for acute COPD flare 50-60 mg/day) A. <2.5 mg A. Increased osteoblast apoptosis (cell death) B. 2.5-5mg B. Increased osteoclast activity C. 7.5mg-12.5 mg C. Decreased osteoblast activation D. >12.5 mg D. Combination of A,B,C 1
Glucocorticoids: Some toxicities Question #3 Diabetes True or False: Cataracts HTN There have been no head to head Weight gain comparative effectiveness studies of Fluid retention bisphosphonates for GIO: PUD Myopathy A. True Psychiatric B. False OSTEOPOROSIS & OSTEONECROSIS 50% of patients Glucocorticoid Effects of Bone Steroids Fracture risk increases with Weinstein R. NEJM 2011;365:62-70 AGE, GENDER, and Dose Increased apoptosis of HIGH osteocytes (bone quality Van Staa et al, decreased before BMD) JBMR, 1998 MEDIUM Prolonged osteoclast survival and decreased osteoclastogenesis Increased Osteoclast bone WOMEN resporption MEN Decreased osteoblastogenesis and increased apoptosis CONTROL Multiple pathways affected!!!! Increased bone resportion relative * to decreased bone formation and decreased overall bone quality: 2
GLUCOCORTICOIDS: “ Double GLUCOCORTICOID - INDUCED Whammy to Bones ” OSTEOPOROSIS Early phase of rapid bone loss (Anti- Resorption) Biophasic effect: Osteoclast effects are early and osteoblast are late – As early as 2 mos into therapy Osteoclast /Pro-resporbtive effects (early) – Resorption markers elevated – Decrease OPG – Pts on high dose prednisone can lose 15-20% of – Increase RANK-L osteoclast #, trabecular bone (spine) in 5-7 mos activity, lifespan Slower phase of bone loss (Anti-Formation) Anti bone-formation effects (late) – Continues indefinitely Decrease osteoblast and osteoclast formation – Trabecular bone especially vulnerable Decrease osteoblast lifespan Enhance apoptosis in osteocytes Relative Rate ( 95% CI) of Non-vertebral Fractures : D/C Steroids Glucocorticoid Effects on Remodeling/Strength (5 years) - REVERSAL RR X many… Manolagas, JBMR , 2000 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 Changes in 2010 ACR Guidelines Weinstein R. NEJM 2011;365:62-70 Expands recommendations for counseling and monitoring to now include: – Fall risk assessment – Height – 25-hydroxyvitamin D measurement – Evaluation for prevalent and incident fragility fractures – Calcium and vitamin D supplementation for any duration of glucocorticoid use. (In addition to 2001 recommendations of smoking cessation, limiting excessive alcohol, weight-bearing activities, and obtaining baseline and follow up BMD measurement) 4
GIO, fracture risk, & effect of other factors: Changes Reflected in ACR 2010 guidelines Glucocorticoids are not given in a vacuum GIO does not occur in a vacuum but interacts with risk factors other than corticosteroids BMD isn ’ t the only means to calculate future fracture risk and therapy has risks Recommendations guided by FRAX score risk, not just BMD Recognize that Frax has limitations (binary yes/no and not cumulative GC use) Weinstein R. NEJM 2011;365:62-70 ACR 2010 Guidelines: Summary of Changes Assessment of 10 Year Fracture Risk ( Scheduled to be updated in 2017) Low Medium High Gives pharmacologic recommendations for three patient categories: – Postmenopausal women and men over age 50 <10% 10-20% >20% – Premenopausal women not of childbearing potential and men under the age of 50 years with a history of a fragility fracture – Premenopausal women of childbearing potential with a history of a fragility fracture. – Insufficient data to make recommendations for premenopausal women and young men at low risk 5
Summary of Updated Pharmacologic Drug Management of GIO Recommendations in ACR 2010 Guidelines Gonadal steroids: testosterone, HRT, SERMS Calcitonin Zoledronic acid and Teriparatide are now Bisphosphonates recommended along with alendronate and Alendronate** risedronate for the treatment of GIOP Risedronate** Zoledronic Acid ** Estrogen replacement and testosterone are no Ibandronate longer endorsed. Pamidronate Anabolic therapy: rh-PTH (1-34)** Data insufficient to recommend use of Biologic Therapy (anti-RANKL) ibandronate, etidronate, calcitonin, estrogen, testosterone, and raloxifene. ** FDA approved Risk Based Approach to Therapy: Post Risk Based Approach to Therapy: Pre menopausal women and Men>50 menopausal women and Men<50 From ACR Clinican ’ s Guide From ACR Clinican ’ s Guide 6
What about Zoledronic Acid? Better than other Horizon Demographics: A bisphosphonates?: Horizon representative population 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 Majority of patients were on more than 7.5mg prednisone a day! Risedronate 5mg Majority of patients had rheumatoid arthritis or SLE Primary endpoint: BMD LS spine Higher risk patients studied – in order to maximize potential effect size PTH vs. bisphosponates: Horizon Results Beneficial for GIO? (2008) Saag et al. NEJM 2007;357:2028-39 36 Month randomized double blinded controlled 18 month interim analysis 428 patients studied – 22-89 years of age – Treated with GC ’ s for at least three months – Prednisone equivalent of 5 mg/day or more – 20 mcg/d PTH vs. 10 mg/d alendronate – Everyone continued Figure 2. Change in mean bone mineral density of lumbar spine and femoral neck for (A) Ca/VitD 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. 7
Who were the Patients? Patients ’ Underlying Disease BMD<-2.0 or <1.0 + fragility fracture (Higher risk patients) Exclusions: Standard for PTH Use Two treatment groups similar (n=214 both) Alendronate PTH Age 57.3 56.1 Prednisone dose 7.8 7.5 Non Vert Frag Fx 20.1% 19.6% BMD T score LS Spine -2.6 -2.5 BMD T score Hip -1.9 -2.0 High risk for fx: higher prednisone dose, lower BMD, and RA/SLE diagnosis PTH vs. Alendronate: Fracture PTH vs. Alendronate Results More than 25% attrition rate in both arms 8
PTH vs. Alendronate 36 month Follow Up: PTH vs. Alendronate: 36 month BMD results Saag et al. Arthritis Rheum. 2009 Nov;60(11):3346-55 fracture follow up Saag et al. Arthritis Rheum. 2009 Nov;60(11):3346-55 PTH At 36 months, statistically significant reduction in both radiographic and clinical vertebral fractures PTH No significant differences in non- vertebral fractures PTH Donosumab (Not FDA approved): PTH for GC induced Osteoporosis: Summary Subgroup analysis from phase 2 trial data Dore et Al. Ann Rheum Dis 2010;69:872-875 PTH appears to improve BMD in GC assoc. osteoporosis – Evidence suggests superior increases in BMD vs. alendronate at hip, femoral neck, and LS spine However, high attrition rate in this study – Nearly 50% drop out in both arms by 36 months – Appears to be of benefit both for clinical and radiographically defined fractures at 36 months – BUT….overall rate of clinical fracture is low in both groups Decrease in fractures limited to vertebral fractures but non- significant for non-vertebral fractures Perhaps consider PTH for those with the most severe GC induced OP and those at highest risk for fracture (such as previous fragility fracture) Patients receiving Donosumab or PBO without exclusions for bisphosphonate use 9
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