Drug-induced osteoporosis Juliet Compston Professor of Bone Medicine University of Cambridge School of Clinical Medicine C...
Drug-induced osteoporosis <ul><li>Glucocorticoids </li></ul><ul><li>Aromatase inhibitors and androgen deprivation therapy ...
Use of glucocorticoids in the UK <ul><li>Oral glucocorticoids used by 0.9% of GPRD population (n=244,235) </li></ul><ul><l...
Bone loss associated with glucocorticoid therapy <ul><li>Most rapid loss in first few months </li></ul><ul><li>of therapy ...
Direct effects of glucocorticoids on bone Increased  bone resorption  Decreased bone formation (early, transient)  (long-t...
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  5...
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 ...
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 Sta...
Effect of interventions on glucocorticoid-induced bone loss and fracture nae: not adequately  assessed nd:  not demonstrat...
Drugs approved for the management  of glucocorticoid-induced osteoporosis <ul><li>Alendronate: given orally, once daily </...
Effect of bisphosphonates on BMD in GIOP: Cochrane analysis <ul><li>13 RCTs involving 842 patients </li></ul><ul><li>Preve...
Similarities and differences between GIOP and PMO GIOP PMO Bone turnover/resorption Increase is early and transient Increa...
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  ...
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 b...
Prevention and treatment of GIOP: can cost-effectiveness be assessed? <ul><li>Limited epidemiological data </li></ul><ul><...
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...
ACR and RCP guidelines for GIOP From Compston, Curr Rheumatol Rep 2004;6:66-9  ACR  RCP (UK) Calcium and vitamin D All pat...
08ca009
Treatment of GIO: unresolved issues <ul><ul><li>Risk assessment and targeting of treatment </li></ul></ul><ul><ul><li>Dura...
Drug-induced osteoporosis <ul><li>Glucocorticoids </li></ul><ul><li>Aromatase inhibitors and androgen deprivation therapy ...
Breast cancer therapy <ul><li>Aromatase inhibitors </li></ul><ul><ul><li>Increase markers of bone turnover </li></ul></ul>...
Androgen deprivation therapy for prostate cancer <ul><li>Most commonly GNRH analogue ± bicalutamide </li></ul><ul><li>Asso...
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...
Effect of anastrozole treatment on fracture risk Median duration of 60 months’ treatment IBMS June 07 p-value <0.0001 0.5 ...
Fracture rates with anastrozole during and after treatment IBMS June 07 Time since randomisation (years) Annual fracture e...
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...
Androgen deprivation therapy and fracture risk IBMS June 07 GnRH therapy and orchiectomy associated with increased bone lo...
Management algorithm for patients with cancer treatment-induced bone loss  Risk assessment with BMD at baseline T score≤ -...
Drug-induced osteoporosis <ul><li>Glucocorticoids </li></ul><ul><li>Aromatase inhibitors and androgen deprivation therapy ...
Depot medroxyprogesterone acetate and skeletal health <ul><li>Depo-provera used as a contraceptive in more than 9 million ...
Drug-induced osteoporosis <ul><li>Glucocorticoids </li></ul><ul><li>Aromatase inhibitors and androgen deprivation therapy ...
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 Veste...
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 y...
Association between osteoporotic fracture and PPI exposure From Targownik et al, CMAJ 2008;179:319-26 Retrospective matche...
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 do...
Effects of H 2  receptor antagonists on fracture risk: conflicting data <ul><li>Yang et al (2006): </li></ul><ul><ul><li>I...
Effect of PPI use on BMD <ul><li>Yu et al (2006): </li></ul><ul><ul><li>Subgroup of women in SOF, prospective with BMD FU ...
Drug-induced osteoporosis <ul><li>Glucocorticoids </li></ul><ul><li>Aromatase inhibitors and androgen deprivation therapy ...
Anti-depressant medication use and  fracture risk Study Result Fracture site SOF (Ensrud et al, 2003) Increased risk for T...
Serotonin (5-hydroxytryptamine) and bone <ul><li>Functional 5-HT transporter demonstrated in osteoblasts, osteocytes and o...
Effect of 5-HTT deficiency in mice (From Warden et al, Endocrinology 2005;146:685-93)
Fracture Free Survival by SSRI Use (Richards et al, Arch Intern Med 2007;167:188-94) HR 2.1(1.3-3.4)
Adjusted % difference in BMD associated with SSRI Use (95% CI) (Richards et al, Arch Intern Med 2007;167:188-94)
The association between SSRI use and falls at baseline interview (Richards et al, Arch Intern Med 2007;167:188-94)
Drug-induced osteoporosis <ul><li>Glucocorticoids </li></ul><ul><li>Aromatase inhibitors and androgen deprivation therapy ...
PPAR  effects on differentiation of osteoblasts and adipocytes  Pluripotent stem cell Osteoblasts Adipocytes -  PPAR ...
Effects of rosiglitazone on bone in healthy postmenopausal women: 14 week RCT <ul><li>13% decrease in P1NP by 4 weeks in r...
Kahn et al, Diabetes Care 2007;31:845-51
<ul><li>Nested case-control study using GPRD </li></ul><ul><li>Use of rosiglitazone, pioglitazone, other oral anti-diabeti...
Summary and conclusions <ul><li>Treatment with a variety of non-skeletal therapies may have adverse effects on bone </li><...
 
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Drug-induced Osteoporosis

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Drug-induced Osteoporosis

  1. 1. Drug-induced osteoporosis Juliet Compston Professor of Bone Medicine University of Cambridge School of Clinical Medicine Cambridge UK
  2. 2. Drug-induced osteoporosis <ul><li>Glucocorticoids </li></ul><ul><li>Aromatase inhibitors and androgen deprivation therapy </li></ul><ul><li>Depo-provera </li></ul><ul><li>Proton pump inhibitors </li></ul><ul><li>Selective serotonin reuptake inhibitors </li></ul><ul><li>Thiazolidenediones </li></ul>
  3. 3. Use of glucocorticoids in the UK <ul><li>Oral glucocorticoids used by 0.9% of GPRD population (n=244,235) </li></ul><ul><li>Highest use (2.5%) in people aged 70-79 years </li></ul><ul><li>Respiratory disease most frequently recorded indication </li></ul><ul><li>Overall use of bone active medications low </li></ul>(from van Staa et al, JBMR 2000; 15: 993-1000)
  4. 4. Bone loss associated with glucocorticoid therapy <ul><li>Most rapid loss in first few months </li></ul><ul><li>of therapy </li></ul><ul><li>Affects cortical and cancellous bone </li></ul><ul><li>Associated with increased fracture risk </li></ul><ul><li>Heterogeneity of individual response </li></ul><ul><li>Potentially reversible </li></ul>
  5. 5. Direct effects of glucocorticoids on bone Increased bone resorption Decreased bone formation (early, transient) (long-term) <ul><li>RANKL </li></ul><ul><li>M-CSF </li></ul><ul><li>PPAR  </li></ul><ul><li>Wnt signalling </li></ul><ul><li>Activation of caspase 3 </li></ul> Formation  Apoptosis  proliferation  apoptosis  apoptosis
  6. 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. 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. 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. 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*
  10. 10. Drugs approved for the management of glucocorticoid-induced osteoporosis <ul><li>Alendronate: given orally, once daily </li></ul><ul><li>Etidronate: given orally, intermittently and cyclically with calcium </li></ul><ul><li>Risedronate: given orally, once daily (approval restricted to postmenopausal women) </li></ul><ul><li>Teriparatide 20 µg daily by s.c. injection </li></ul>
  11. 11. Effect of bisphosphonates on BMD in GIOP: Cochrane analysis <ul><li>13 RCTs involving 842 patients </li></ul><ul><li>Prevention and treatment studies included </li></ul><ul><li>RR vertebral fracture 0.76 (0.37-1.53) </li></ul><ul><li>Homik et al, 2000 Cochrane </li></ul><ul><li>Database Systematic Review </li></ul><ul><li> </li></ul>0 1 2 3 4 5 6 LS FN Mean weighted difference % (2.5,5.5) (0.2,4.0) BMD
  12. 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. 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. 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
  15. 15. Prevention and treatment of GIOP: can cost-effectiveness be assessed? <ul><li>Limited epidemiological data </li></ul><ul><li>Diversity of dosing regimens used in clinical practice </li></ul><ul><li>No primary non-vertebral fracture efficacy data available </li></ul><ul><li>Disutility and mortality of fractures not documented in GC users </li></ul><ul><li>Impact of side-effects not well documented </li></ul>
  16. 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. 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. 18. 08ca009
  19. 19. Treatment of GIO: unresolved issues <ul><ul><li>Risk assessment and targeting of treatment </li></ul></ul><ul><ul><li>Duration of use </li></ul></ul><ul><ul><li>Indications in intermittent glucocorticoid use, inhaled glucocorticoids </li></ul></ul><ul><ul><li>Use in children </li></ul></ul><ul><ul><li>Monitoring of treatment response </li></ul></ul>
  20. 20. Drug-induced osteoporosis <ul><li>Glucocorticoids </li></ul><ul><li>Aromatase inhibitors and androgen deprivation therapy </li></ul><ul><li>Depo-provera </li></ul><ul><li>Proton pump inhibitors </li></ul><ul><li>Selective serotonin reuptake inhibitors </li></ul><ul><li>Thiazolidenediones </li></ul>
  21. 21. Breast cancer therapy <ul><li>Aromatase inhibitors </li></ul><ul><ul><li>Increase markers of bone turnover </li></ul></ul><ul><ul><li>Increased rates of bone loss in some studies </li></ul></ul><ul><ul><li>Effect on fracture risk unclear </li></ul></ul><ul><li>Tamoxifen </li></ul><ul><ul><li>Bone protective in postmenopausal skeleton </li></ul></ul><ul><ul><li>Associated with bone loss in premenopausal women </li></ul></ul><ul><li>Gonadotrophin-releasing hormone analogues </li></ul><ul><ul><li>Associated with rapid bone loss in premenopausal women </li></ul></ul>
  22. 22. Androgen deprivation therapy for prostate cancer <ul><li>Most commonly GNRH analogue ± bicalutamide </li></ul><ul><li>Associated with increased rates of bone loss </li></ul><ul><li>No prospective fracture data but evidence from observational studies for increased fracture incidence </li></ul>
  23. 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. 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. 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. 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. 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. 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
  29. 29. Drug-induced osteoporosis <ul><li>Glucocorticoids </li></ul><ul><li>Aromatase inhibitors and androgen deprivation therapy </li></ul><ul><li>Depo-provera </li></ul><ul><li>Proton pump inhibitors </li></ul><ul><li>Selective serotonin reuptake inhibitors </li></ul><ul><li>Thiazolidenediones </li></ul>
  30. 30. Depot medroxyprogesterone acetate and skeletal health <ul><li>Depo-provera used as a contraceptive in more than 9 million women world-wide </li></ul><ul><li>Use is associated with reduced serum oestradiol levels and increase in biochemical markers of bone turnover </li></ul><ul><li>Low bone density and bone loss have been demonstrated in adolescents using depo-provera, with recovery on withdrawal </li></ul><ul><li>No fracture data available </li></ul>
  31. 31. Drug-induced osteoporosis <ul><li>Glucocorticoids </li></ul><ul><li>Aromatase inhibitors and androgen deprivation therapy </li></ul><ul><li>Depo-provera </li></ul><ul><li>Proton pump inhibitors </li></ul><ul><li>Selective serotonin reuptake inhibitors </li></ul><ul><li>Thiazolidenediones </li></ul>
  32. 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. 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. 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. 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
  36. 36. Effects of H 2 receptor antagonists on fracture risk: conflicting data <ul><li>Yang et al (2006): </li></ul><ul><ul><li>Increased risk of hip fracture with ≥ I yr use </li></ul></ul><ul><li>Vestergaard et al (2006): </li></ul><ul><ul><li>Decreased risk of all fractures and hip fracture with use in past year </li></ul></ul>0 0.2 0.4 0.6 0.8 1 1.2 1.4 Yang et al 2006 JAMA,296:2947-53 Vestergaard et al 2006 CTI;79:76-83 All # Hip #
  37. 37. Effect of PPI use on BMD <ul><li>Yu et al (2006): </li></ul><ul><ul><li>Subgroup of women in SOF, prospective with BMD FU of 4.9 yrs </li></ul></ul><ul><ul><li>No difference in hip BMD or rate of bone loss between PPI users and non-users </li></ul></ul><ul><li>Bauer et al (2006): </li></ul><ul><ul><li>MrOS study, prospective with BMD FU of 3.4 yrs </li></ul></ul><ul><ul><li>Significantly lower LS BMD in PPI users </li></ul></ul><ul><ul><li>Trend to higher rates of bone loss in PPI users </li></ul></ul><ul><li> </li></ul>0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 Yu et al JBMR 2006; 21 (suppl 1) S281 Bauer et al 2006 HR non-spine fracture 1.01-1.39 0.98-2.30
  38. 38. Drug-induced osteoporosis <ul><li>Glucocorticoids </li></ul><ul><li>Aromatase inhibitors and androgen deprivation therapy </li></ul><ul><li>Depo-provera </li></ul><ul><li>Proton pump inhibitors </li></ul><ul><li>Selective serotonin reuptake inhibitors </li></ul><ul><li>Thiazolidenediones </li></ul>
  39. 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
  40. 40. Serotonin (5-hydroxytryptamine) and bone <ul><li>Functional 5-HT transporter demonstrated in osteoblasts, osteocytes and osteoclasts </li></ul><ul><li>Bone cells express mRNA from tryptophan hydroxylase - thus potentially capable of synthesising 5-HT </li></ul><ul><li>5-HT receptors are present in bone cells </li></ul><ul><li>In vitro evidence that 5-HT may have stimulatory effects on bone formation and reduce bone resorption </li></ul>
  41. 41. Effect of 5-HTT deficiency in mice (From Warden et al, Endocrinology 2005;146:685-93)
  42. 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. 43. Adjusted % difference in BMD associated with SSRI Use (95% CI) (Richards et al, Arch Intern Med 2007;167:188-94)
  44. 44. The association between SSRI use and falls at baseline interview (Richards et al, Arch Intern Med 2007;167:188-94)
  45. 45. Drug-induced osteoporosis <ul><li>Glucocorticoids </li></ul><ul><li>Aromatase inhibitors and androgen deprivation therapy </li></ul><ul><li>Depo-provera </li></ul><ul><li>Proton pump inhibitors </li></ul><ul><li>Selective serotonin reuptake inhibitors </li></ul><ul><li>Thiazolidenediones </li></ul>
  46. 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)
  47. 47. Effects of rosiglitazone on bone in healthy postmenopausal women: 14 week RCT <ul><li>13% decrease in P1NP by 4 weeks in rosiglitazone group </li></ul><ul><li>8% fall in osteocalcin </li></ul><ul><li>No significant change in markers of resorption </li></ul>-2 -1.8 -1.6 -1.4 -1.2 -1 -0.8 -0.6 -0.4 -0.2 0 TH RGZ Placebo (from Grey et al, JCEM 2007;92:1305-10) LS p<0.01 ns % change in BMD
  48. 48. Kahn et al, Diabetes Care 2007;31:845-51
  49. 49. <ul><li>Nested case-control study using GPRD </li></ul><ul><li>Use of rosiglitazone, pioglitazone, other oral anti-diabetic drugs and insulin included </li></ul><ul><li>Association with fracture shown only for the TZDs </li></ul><ul><li>Meier et al, Arch Intern Med 2008;168:820-5 </li></ul>Effect of thiazolidenediones on fracture risk 1 1.5 2 2.5 3 All Rosi Pio 1.39,4.09 0.96,7.01 1.49,3.95
  50. 50. Summary and conclusions <ul><li>Treatment with a variety of non-skeletal therapies may have adverse effects on bone </li></ul><ul><li>In general, where increased fracture risk has been demonstrated the effect is relatively small </li></ul><ul><li>Most but not all of these effects have biologically plausible mechanisms </li></ul><ul><li>In clinical practice the potentially adverse skeletal effects of these drugs must be weighed against their benefits </li></ul>

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