1. Drug-induced osteoporosis Juliet Compston Professor of Bone Medicine University of Cambridge School of Clinical Medicine Cambridge UK

6. Glucocorticoids increase fracture risk independently of BMD 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 OP fracture Hip fracture 50 55 60 65 70 75 80 Age (yrs) BMD-adjusted RR (from Kanis et al, JBMR 2004;19:893-7)

7. Use of oral glucocorticoids and risk of fracture 0 1 2 3 4 5 6 Hip Spine 0.8-1.2 1.2-2.0 1.6-2.0 2.2-3.1 1.9-2.7 4.3-6.3 (from van Staa et al 2000;15:993-1000) RR < 2.5 mg/d 2.5 - 7.5 mg/d > 7.5 mg/d N=244,235 Mean age 57 yr 59% female

8. Time course of vertebral fractures during glucocorticoid use 0 0.5 1 1 year before 0-3 3-6 6-9 9-12 Months % (from van Staa et al, OI 2002;13:777-87) >7.5 mg daily 2.5 - 7.5 mg daily <2.5 mg daily

9. Effect of interventions on glucocorticoid-induced bone loss and fracture nae: not adequately assessed nd: not demonstrated *: not a 1˚ end-point #: data inconsistent Intervention Spine BMD Proximal femur BMD Vertebral fracture Alendronate A A A * Alfacalcidol A A  nae Calcitonin A  A  nae Calcitriol A  A  nae Calcium nd nd nae Calcium + vitamin D A  A  nae Clodronate A A nae Cyclic etidronate A A A * Fluoride A nd nae Ibandronate A A A* Pamidronate A A nae PTH A A nae Raloxifene no data no data no data Risedronate A A A * Teriparatide A A A*

12. Similarities and differences between GIOP and PMO GIOP PMO Bone turnover/resorption Increase is early and transient Increased long-term Bone formation at BMU level Reduced ++ Reduced + Fracture risk Increase mainly in first few months Risk increases with time Distribution of bone loss Cancellous and cortical sites Cancellous and cortical sites

13. Comparison of efficacy of bisphosphonates in PMO and GIOP 0.0 0.5 1.0 1.5 2.0 PMO GIO PMO GIO RR N = 9,681 987 14,551 500 Vertebral fracture Non-vertebral fracture RR= 0.58 0.48 0.81 0.79 From Kanis et al, Health Tech Assess 2007;11:1-258

14. Effects of teriparatide and alendronate on lumbar spine BMD M o n t h s 0 3 6 1 2 1 8 E n d p o i n t Mean % change from baseline ± SE 0 2 4 6 8 1 0 T e r i p a r a t i d e A l e n d r o n a t e Alendronate N= 195 184 173 159 148 195 Teriparatide N= 198 183 178 170 156 198 ‡ P<0.001 Teriparatide vs. Alendronate ‡ ‡ ‡ ‡ Saag KG et al. N Eng J Med 2007; 357:2028-39

16. Cost-effectiveness of bisphosphonates in GIOP 0 20 40 60 80 100 0 20 40 60 80 100 Cost (£000)/QALY gained 0 20 40 60 80 100 0 20 40 60 80 100 Cost (£000)/QALY gained 0 20 40 60 80 100 -10 0 10 20 30 40 50 Cost (£000)/QALY gained 0 20 40 60 80 100 -20 -10 0 10 20 30 40 50 Cost (£000)/QALY gained Age=80 years No prior fracture Prior fracture Age=70 years Age=50 years Age=60 years Cumulative frequency (%) T-score = -2.5 T-score = -2.5 T-score = -2.5 T-score = -2.5 From Kanis et al, Health Tech Assess 2007;11:1-258

17. ACR and RCP guidelines for GIOP From Compston, Curr Rheumatol Rep 2004;6:66-9 ACR RCP (UK) Calcium and vitamin D All patients Those with low ca intake and/or vit D insufficiency Bisphosphonates for 1˚ prevention All patients taking GCs ≥ 5mg/d for 3 months Age ≥ 65yrs PH fragility fracture Bisphosphonates for 2˚ prevention BMD T-score ≤-1 BMD T-score ≤ -1.5

18. 08ca009

23. Annualised rates of bone loss (lumbar spine) IBMS June 07 0 3 6 9 Annual LS-BMD loss (%) Normal men Late PM women Early PM women Aromatase inhibitor (AI) Androgen deprivation therapy Gonadorelin plus AI Treatment induced ovarian failure Guise, T. A. Oncologist 2006;11:1121-1131

24. Effect of anastrozole treatment on fracture risk Median duration of 60 months’ treatment IBMS June 07 p-value <0.0001 0.5 0.03 0.4 <0.0001 Any fracture Hip Spine Wrist / Colles All other sites Number of patients (%) ATAC Trialists’ Group. Lancet 2005;365:60-62 Anastrozole (n=3092) 340 (11.0) 37 (1.2) 45 (1.5) 72 (2.3) 220 (7.1) Tamoxifen (n=3094) 237 (7.7) 31 (1.0) 27 (0.9) 63 (2.0) 142 (4.6)

25. Fracture rates with anastrozole during and after treatment IBMS June 07 Time since randomisation (years) Annual fracture episode rates (%) Tamoxifen (T) Anastrozole (A) 0 1 2 3 4 5 6 7 8 9 0 2 3 4 1 The ATAC Trialists’ Group. Lancet Oncol 2008; 9: 45-53

26. Fracture risk in men treated with ADT Vertebral fractures RR 1.45 (1.19,1.75) Hip/femur fractures RR 1.30 (1.10,1.53) From Smith et al, J Clin Oncol 2005 Retrospective study Using Medicare claims data

27. Androgen deprivation therapy and fracture risk IBMS June 07 GnRH therapy and orchiectomy associated with increased bone loss at spine and hip. Relative risk of fracture increased by up to 50-60% All skeletal sites affected Shahinian et al, NEJM 2005 50,613 men in the Surveillance, Epidemiology, and End Results (SEER) program with diagnosis of prostate cancer from 1992 through 1997

28. Management algorithm for patients with cancer treatment-induced bone loss Risk assessment with BMD at baseline T score≤ -2.5 Repeat BMD at 5 yrs Treat: ADT: alendronate zoledronic acid AIs: risedronate zoledronic acid T score≥ -1 T score≤ -1 to -2.5 Reassure Reassess risk at 1-2 yrs No other risk factors Other risk factors

32. Effect of proton pump inhibitors on fracture risk 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 All Hip Spine Odds ratio (from Vestergaard et al, CTI 2006;79:76-83) 1.12-1.43 1.28-1.65 1.25-2.04 124,655 cases 373,962 controls

33. Effect of proton pump inhibitors on hip fracture risk according to duration of use 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 1 yr 2 yrs 3 yrs 4 yr s (from Yang et al, JAMA 2006;296:2947-53) Adjusted odds ratio 1.15-1.30 1.28-1.56 1.37-1.73 1.39-1.80 13,556 hip # 135,386 controls

34. Association between osteoporotic fracture and PPI exposure From Targownik et al, CMAJ 2008;179:319-26 Retrospective matched cohort study using claims databases

35. PPIs and fracture risk: GPRD data 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 Any Fragility Hip Wrist Low dose Medium dose High dose Spine * * * * * * * * Adjusted OR Data courtesy of Cyrus Cooper

39. Anti-depressant medication use and fracture risk Study Result Fracture site SOF (Ensrud et al, 2003) Increased risk for TCAs and SSRIs Non-spine fractures MrOS (Lewis et al, 2007) Increased risk with TCAs Non-spine fractures CaMOS (Richards et al, 2007) Increased risk with SSRIs Clinical fractures Danish study (Vestergaard et al, 2006) Increased risk for TCAs and SSRIs Clinical fractures GPRD (UK) (Hubbard et al, 2003) Increased risk for TCAs and SSRIs Hip fractures WHI (Spangler et al, 2008) Increased risk for SSRIs All clinical fractures

41. Effect of 5-HTT deficiency in mice (From Warden et al, Endocrinology 2005;146:685-93)

42. Fracture Free Survival by SSRI Use (Richards et al, Arch Intern Med 2007;167:188-94) HR 2.1(1.3-3.4)

43. Adjusted % difference in BMD associated with SSRI Use (95% CI) (Richards et al, Arch Intern Med 2007;167:188-94)

44. The association between SSRI use and falls at baseline interview (Richards et al, Arch Intern Med 2007;167:188-94)

46. PPAR  effects on differentiation of osteoblasts and adipocytes Pluripotent stem cell Osteoblasts Adipocytes - PPAR  (from Cock et al, EMBO reports, 2004;5:1007-12)

48. Kahn et al, Diabetes Care 2007;31:845-51