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Osteoporosis and Fracture Risk Reduction comep oct 2010

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  • 1. Alastair R. McLellan MD, FRCP Western Infirmary, Glasgow Core Medical Training Osteoporosis & fracture risk reduction
  • 2.  
  • 3. In UK >250,000 osteoporosis-related fractures per year Annual cost >£ 1.7 billion
  • 4.
    • Osteoporosis & fracture epidemiology
    • Treatment options & what’s new
    • How to use treatments
    • Treatment – emerging side effects
    • Osteoporosis & the receiving physician
    Osteoporosis & fracture risk reduction
  • 5.
    • Osteoporosis & fracture epidemiology
    • Treatment options & what’s new
    • How to use treatments
    • Treatment – emerging side effects
    • Osteoporosis & the receiving physician
    Osteoporosis & fracture risk reduction
  • 6. Which site of fracture accounts for most clinical fracture presentations in patients age ≥50yr?
  • 7. FLS: 8yr WIG: 8668F & 2428M =11096
  • 8. Which is the commonest site of new fracture in patients age 50 & over?
  • 9. North Glasgow FLS 1999-2007 22502 fracture presentations
  • 10. Vertebral fractures: the paradox Commonest fracture but seldom identified …… .why?
  • 11. Definition of vertebral fracture?
  • 12. Definition of vertebral fracture HEIGHT LOSS SHAPE CHANGE ENDPLATE CHANGE
  • 13. Definition of vertebral fracture used in the clinical trials Height Loss % Absolute Change in SQ Grading ALENDRONATE RALOXIFENE CALCITONIN IBANDRONATE ZOLEDRONIC ACID ≥ 20% ≥ 4mm ≥ 1 RISEDRONATE ≥ 15% ≥ 4mm ≥ 1 1-34 PTH 0 to 1+
  • 14. Vertebral fractures: the paradox
    • Why?
    • Presentations of vertebral fractures
    • Access to imaging
    • Radiologists & reporting
    McLellan et al: http://www.nhshealthquality.org/nhsqis
  • 15. Vertebral Fractures
  • 16. Vertebral fractures: under-diagnosed Gehlbach et al.,Osteoporos Int 2000, 11:577 934 hospitalised women with a lateral chest x-ray 0 20 40 60 80 100 120 140 Patients (n) 132 65 23 25 Fracture identified by study radiologists Fracture noted in radiology report Fracture noted in medical record Received osteoporosis treatment
  • 17.  
  • 18. Prevalence of Vertebral Deformities : Age & Gender (EVOS study) Ismail et al. O.I. 1999; 9: 206-213
  • 19. Incidence rates for vertebral, wrist & hip fractures in women after age 50 Wasnich RD, Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th edition, 1999
  • 20.  
  • 21. Epidemiology of Osteoporotic Fractures in UK Dennison & Cooper BJCP 1996:50;33 Hip Spine Wrist Lifetime Risk (%) Women (@50yr) 14 11 13 Men (@50yr) 3 2 2 Mean Age (yr) 79 67 65 Mortality (relative survival)
  • 22. MORBIDITY MORTALITY FRACTURES
  • 23. Cumulative Survival Probability Center JR et al., Lancet 1999, 353:878 Age MEN Survival probability 60 65 70 75 80 85 Age WOMEN Survival probability 60 65 70 75 80 85 0.2 0.4 0.6 0.8 0 1.0 Dubbo Population Vertebral/Major Fractures Proximal Femur Fractures 1.0 0 0.2 0.4 0.6 0.8
  • 24. a fracture at any site is associated with 2-3x increased risk of further fracture at any skeletal site
  • 25. Among women with hip fracture: 45% have had ≥1 previous fracture 18% will have ≥1 further fracture in next 2 yr Previous fractures since age of 50 yr Fractures during 1.8 (0.6) yr follow-up [0.5–3.1 yr] 45% 18% % www.nhshealthquality.org/nhsqis
  • 26. Risk factors for fracture & opportunities to intervene?
  • 27. OSTEOPOROSIS FRACTURES RISK FACTORS FOR O SKELETAL BONE MINERAL DENSITY Hip geometry - HAL U/S characteristics Microarchitecture Bone turnover SKELETAL/ FALL AGE Genetic Maternal hip # FRACTURE HISTORY Height Smoking Weight change FALL neuromuscular problems cognition visual impairment drug therapy fall mechanics R I S K F A C T O R S F O R #
  • 28. OSTEOPOROSIS FRACTURES RISK FACTORS FOR O SKELETAL BONE MINERAL DENSITY SKELETAL/ FALL AGE FRACTURE HISTORY FALL R I S K F A C T O R S F O R # Target Group Modifiable with Falls Reduction Strategy Modifiable If Target Rx Using Axial DXA
  • 29.
    • Osteoporosis & fracture epidemiology
    • Treatment options & what’s new
    • How to use treatments
    • Treatment – emerging side effects
    • Osteoporosis & the receiving physician
    Osteoporosis & fracture risk reduction
  • 30. Anti-resorptive Anabolic ‘ Dual action’
  • 31. Treatments & Efficacy Yes Yes Yes Risedronate* Yes Yes Yes HRT Yes Etidronate* Yes Yes Yes Alendronate* [Yes] Yes Ibandronate* Yes Raloxifene* Yes Calcitriol* Yes Other Fx Hip Fx [Yes] Yes Strontium Ranelate * Oral Non-vertebral Fx Vertebral Fx
  • 32. Yes 1-84 PTH* Yes Yes Yes Zoledronate* Intranasal or Subcutaneous Yes Yes Other Fx Hip Fx Yes Calcitonin* Ibandronate* Pamidronate Intravenous Yes Yes Denosumab* Yes Teriparatide* Subcutaneous Non-vertebral Fx Vertebral Fx
  • 33. Appropriate use of appropriate treatments can halve the incidence of fractures * plus calcium + vitaminD ??? Yes Yes Strontium ranelate* Yes Yes Yes Denosumab* Vertebral Fx Nonvertebral Fx Other Fx Hip Fx Alendronate* Yes Yes Yes Risedronate* Yes Yes Yes Zoledronic acid* Yes Yes Yes PTH* Yes Yes ???
  • 34. Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis Dennis M. Black, Ph.D., Pierre D. Delmas, M.D., Ph.D., Richard Eastell, M.D., Ian R. Reid, M.D., Steven Boonen, M.D., Ph.D., Jane A. Cauley, Dr.P.H., Felicia Cosman, M.D., Péter Lakatos, M.D., Ph.D., Ping Chung Leung, M.D., Zulema Man, M.D., Carlos Mautalen, M.D., Peter Mesenbrink, Ph.D., Huilin Hu, Ph.D., John Caminis, M.D., Karen Tong, B.S., Theresa Rosario-Jansen, Ph.D., Joel Krasnow, M.D., Trisha F. Hue, M.P.H., Deborah Sellmeyer, M.D., Erik Fink Eriksen, M.D., D.M.Sc., Steven R. Cummings, M.D., for the HORIZON Pivotal Fracture Trial 2007 Volume 356:1809-1822 The NEW ENGLAND JOURNAL of MEDICINE
  • 35. Study Population & Primary End Points
      • Inclusion
      • Women 65 to 89 years of age
      • Femoral neck T-score ≤–2.5 with or without fracture or ≤–1.5 with 2 mild or 1 moderate vertebral fracture
      • Primary Efficacy End Points
    • Reduction in vertebral fracture over 3 years
    • Reduction in time to hip fracture over 3 years
    Black DM, et al. N Engl J Med . 2007;356:1809-1822
  • 36. Zoledronic Acid Reduced Cumulative 3-Year Risk of Clinical Fractures (Hip, Clinical Vertebral, Non-vertebral) Values above bars are 3-year cumulative event rates based on Kaplan-Meier estimates. * P = .0024; † P < .0001; ‡ P = .0002; relative risk reduction vs placebo § Hip fracture was not excluded from analysis of non-vertebral fracture. 41%* (17%, 58%) 77%† (63%, 86%) 25%‡ (13%, 36%) Clinical Vertebral Fracture Hip Fracture Non-vertebral Fracture § 1.4% (52/3875) 0.5% (19/3875) 2.5% (88/3861) 2.6% (84/3861) 8.0% (292/3875) 10.7% (388/3861) Cumulative Incidence (%) of New Clinical Fractures Over 3 Years 0 10 5 15 Black DM, et al. N Engl J Med . 2007;356:1809-1822. ZOL 5 mg Placebo
  • 37. Horizon RFT Paldeep Atwal
  • 38. Paldeep Atwal
  • 39. Overview
    • Event-driven, randomised, double-blind, placebo-controlled clinical trial
      • 2127 men and women from 148 clinical centres in 23 countries
    • Treatment
      • Annual infusion of either ZOL 5 mg or placebo
      • Loading dose of vitamin D 75,000–125,000 IU/d
      • Calcium 1000–1500 mg/d; vitamin D 400–1200 IU/d
    • Follow-up visits at 6, 12, 24, and 36 months
      • Telephone interviews every 3 months starting at month 9
  • 40. Primary and Secondary Efficacy End Points
    • Primary Objective
      • Reduce the fracture rate of new clinical fractures after surgical procedure for a low-trauma hip fracture
    • Secondary Objectives
      • Reduce the risk of clinical vertebral, hip, and non-vertebral fracture
      • Increase BMD at the total hip and femoral neck of the non-fracture hip at months 12 and 24
      • Reduce subsequent hospitalisations
  • 41. Study Population
    • Inclusion
      • Male or female patients aged 50 years and older
      • Randomised up to 90 days after surgical procedure for a low-trauma hip fracture
      • Ambulatory prior to hip fracture
    • Exclusion
      • Use of oral bisphosphonates
      • Calculated creatinine clearance <30 mL/min
      • Hypercalcaemia (≥2.75 mmoL/L)
      • Hypocalcaemia (corrected calcium <2.0 mmol/L)
      • Primary hyperparathyroidism, hypoparathyroidism, osteogenesis imperfecta, Paget’s disease
      • Any prior use of IV bisphosphonate (within 2 years)
      • Any prior use of parathyroid hormone and analogs for >1 week
  • 42. Conclusions
    • In subjects treated within 90 days after surgical repair of a hip fracture, ZOL 5 mg:
      • Reduced risk of overall clinical fractures by 35% (RR)
        • Multiple clinical fractures by 33%
        • Clinical vertebral fractures by 46%
        • Non-vertebral fracture by 27%
    • 30% lower rate of hip fractures (NS vs placebo)
      • Reduced mortality risk by 28%
      • Increased total hip and femoral neck BMD at all time points
      • Generally safe and well tolerated
    • Incidence of AEs and SAEs comparable to placebo
      • Incidence of AEs and SAEs comparable to placebo
      • No evidence of long-term effect on renal function
      • 20% reduction in risk of atrial fibrillation/atrial flutter SAEs
  • 43. 2007 Volume 357:1799-1809 Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture Kenneth W. Lyles, M.D., Cathleen S. Colón-Emeric, M.D., M.H.Sc., Jay S. Magaziner, Ph.D., Jonathan D. Adachi, M.D., Carl F. Pieper, D.P.H., Carlos Mautalen, M.D., Lars Hyldstrup, M.D., D.M.Sc., Chris Recknor, M.D., Lars Nordsletten, M.D., Ph.D., Kathy A. Moore, R.N., Catherine Lavecchia, M.S., Jie Zhang, Ph.D., Peter Mesenbrink, Ph.D., Patricia K. Hodgson, B.A., Ken Abrams, M.D., John J. Orloff, M.D., Zebulun Horowitz, M.D., Erik Fink Eriksen, M.D., D.M.Sc., Steven Boonen, M.D., Ph.D., for the HORIZON Recurrent Fracture Trial The NEW ENGLAND JOURNAL of MEDICINE
  • 44. Zoledronic Acid Reduced Cumulative Risk of Clinical Fractures by 35% Over Time ZOL N=1065 1013 950 895 762 628 473 316 212 129 PBO N=1062 1010 947 884 742 611 443 305 190 119
  • 45. Zoledronic acid reduced risk of all-cause mortality by 28% over time ZOL N=1054 1029 987 943 806 674 507 348 237 144 PBO N=1057 1028 993 945 804 681 511 364 236 149
  • 46. Denosumab Amanda Fitzpatrick
  • 47.
    • Denosumab (Prolia ™)
    • RANK (Receptor activator of nuclear factor kappa) receptors are found on pre-osteoclasts. They are activated by binding of the RANK ligand (RANKL), allowing osteoclast maturation
    • Osteoprotegerin (OPG) is a natural inhibitor of RANK-RANKL binding, so inhibits bone resorption. Found to stimulated in vivo by oestrogen.
    • Denosumab, fully human monoclonal IgG antibody, binds RANK and prevents RANKL activation
  • 48. FREEDOM trial
    • FREEDOM = F racture RE duction E valuation of D enosumab in O steoporosis every 6 M onths
    • Denosumab 60mg s/c injection 6 mthly for 3 years vs placebo. Randomisation age-stratified.
    • 7868 p atients, age 60 – 90yrs old, with T score hip/lumbar spine between -2.5 to -4.0.
    • Primary aim: reduction in vertebral fractures
    • Exclusion criteria: bisphosphonates within past 12 months, more than 2 moderate or 1 severe vertebral fracture
    • All subjects received calcium and vitamin D supplements
  • 49. Results 1. 68% reduction in relative risk of new vertebral fracture 2. 20% reduction in incidence of non-vertebral fractures, and 40% reduction in hip fracture
  • 50. 3. Increase over time in BMD lumbar spine (9%) and hip (6%) 3. Bone resorption reduced by 86% at 1 month (serum CTX) and maintained
  • 51.
    • Short and long term AE’s : previous studies suggested ↑ infections, ↑ eczema, possible ↑ malignancy however no evidence from FREEDOM study.
    • Effectiveness is similar to that of zolendronate, and greater than oral bisphosphonates
    • Cost : £1000 per patient/year, compare to alendronate £50/year, zolendronate £250/year
    • Other positive trials of Denosumab
      • Reduced vertebral #s by 62% prostate Ca patients receiving hormone deprivation therapy (n= 1468)
      • Smaller studies in bone metastases related to prostate, breast and other malignancies
      • Benefits to cortical bone (radius) in PM women
      • In RA: two randomised trials demonstrate increase in hand bone mineral density, total around 300 patients
  • 52. Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis Cummings, S.R. et al N Engl J Med 2009: 361(8):756-765 7868 women, 60-90yr LS or TH T-score: -2.5 to -4 60mg sc denosumab v PBO 6monthly for 36months +1000mgCa/vitD 1 y endpoint New vertebral fracture 2 y endpoint Non-vertebral & hip fractures
  • 53. Baseline Characteristics Cummings SR et al. N Engl J Med 2009;361:756-765
  • 54. Effect of Denosumab on the Risk of Fracture at 36 Months Cummings SR et al. N Engl J Med 2009;361:756-765
  • 55. % Changes in BMD & Markers of Bone Turnover Cummings SR et al. N Engl J Med 2009;361:756-765
  • 56. Incidence of New Vertebral, Nonvertebral, and Hip Fractures Cummings SR et al. N Engl J Med 2009;361:756-765
  • 57. Adverse Events Cummings SR et al. N Engl J Med 2009;361:756-765
  • 58.  
  • 59. Table 1: Cost for 28 days treatment (Scottish Drug Tariff May 2007 / BNF March 2007) 271.88 Teriparatide (Forsteo®) 20mcg daily 25.60 Strontium ranelate (Protelos®) 2g daily 23.15 Alendronic acid (generic) 10mg daily 23.12 Alendronic acid (Fosamax®) 10mg daily 22.80 Alendronic acid 70mg & Vit D3 2800 i.u.(Fosavance®) * 22.80 Alendronic acid (Fosamax®) 70mg weekly 21.45 Ibandronic acid (Bonviva®) 150mg monthly * 20.30 Risedronate (Actonel®) 35mg weekly 19.10 Risedronate (Actonel®) 5mg daily 17.06 Raloxifene (Evista®) 60mg daily * 3.66 Alendronic acid (generic) 70mg weekly Cost (£) Drugs
  • 60.
    • Osteoporosis & fracture epidemiology
    • Treatment options & what’s new
    • How to use treatments
    • Treatment – emerging side effects
    • Osteoporosis & the receiving physician
    Osteoporosis & fracture risk reduction
  • 61. When is treatment required?
  • 62. Future fracture risk determines need for treatment
  • 63. DXA
  • 64. FRAX Cathy Anderson
  • 65. FRAX in osteoporosis treatment Dr Cathy Anderson CT2 28/09/10
  • 66. FRAX
    • WHO developed, computer driven, calculation tool ( www.sheffield.ac.uk/FRAX/index.jsp )
    • Predicts the 10 year probability of both hip fracture and all major osteoporotic fracture
    • Based on clinical risk factors with the option of including Bone Mineral Density at femoral neck to increase the accuracy
    • Developed on individual patient models and allows selection based on gender and nationality.
  • 67. FRAX Tool
    • Select Tool appropriate to nationality
    • Enter: Age, sex, weight (kg), height (cm)
    • Answer ‘yes/no’ to
    • Previous fracture?
    • Parent fracture?
    • Current smoker?
    • Glucocorticoid use? (current or > 3 months)
    • RA diagnosis?
    • Secondary osteoporosis?
    • Alcohol intake > 3 units/day
    • Enter Femoral Neck BMD g/cm 2 if known
  • 68. Interpretation
    • Tool calculates
      • BMI
      • 10 year hip # probability
      • 10 year major osteoporotic # probability
    • Links to the National Osteoporosis Guidelines Group (NOGG) website where it plots your result on a risk stratification graph that advises low, intermediate or high risk.
  • 69. Problems
    • Doesn’t allow for multiple previous fractures (increased risk) or for specification of site of previous fracture.
    • Doesn’t specify dose of glucocorticoid
    • Doesn’t allow for uncertainty as to whether patient has a risk factor or not
    • Doesn’t include falls risk
    • Doesn’t account for ethnic minorities
  • 70. Treatment Decisions
    • Only intended as an aid to treatment decisions
    • Low – reassure, lifestyle advice and repeat in 5 years
    • Intermediate – measure BMD and recalculate
    • High – Consider treatment
    • Treatment will depend on local factors linked to cost effectiveness – take into account cost of fracture, cost of risk factor management, cost of treatment, health care allowance locally.
  • 71.  
  • 72.
    • 55yr female
    • Colles’ fracture
    • Smoker 20cigs
    • Maternal hip fracture age 75yr
    • Should she receive treatment for fracture secondary prevention?
  • 73.  
  • 74.
    • 55yr female
    • Colles’ fracture
    • Smoker 20cigs
    • Maternal hip fracture age 75yr
    • FRAX major fx = 19%, hip fx = 2.8%
    • Fracture Risk if
    • FN T-score = +2
    • FN T-score = +1
    • FN T-score = 0
    • FN T-score = -1
    • FN T-score = -2.5
    • FN T-score = -3
  • 75.  
  • 76.  
  • 77. FRAX
    • Pros
    • Quantitation of fracture risk facilitates communication & understanding
    • Easy to use
    • Cons
    • FRAX fracture risk doesn’t imply that treatment can modify that risk
    • Non-vertebral fracture risk can only be reduced in those <70 when T-score <-2.
    • Doesn’t work if lowest T-score is at spine
    • Underestimates fracture risk if >1 previous fracture
  • 78.  
  • 79.  
  • 80. ALN only prevents nonvertebral fractures in osteoporotic women Cummings et al JAMA 1998; 280: 2077-2082 FITII: Pre-planned analysis: 2214 ALN v 2218 PBO, 4.2yr follow up Only in those with osteoporosis 63 clinical fractures (incl 12 hip) prevented per 1000 women yrs’ Rx plus 27 radiographic vertebral fractures prevented PBO PBO ALN ALN
  • 81. FN T-score n HRT ? BZD 43 IBAN ? CLO 18 ALN 19 FOSIT RIS 22 (12hip) HIP ALN 63 (12hip) FITII CLO 5 RIS ? HRT 3
  • 82. Guidelines & treatment decisions
  • 83.  
  • 84. http://www.sign.ac.uk/guidelines/fulltext/71/index.html
  • 85.  
  • 86.  
  • 87. Prevalence of Osteoporosis in Women & Men with Fractures I %
  • 88.
    • Osteoporosis & fracture epidemiology
    • Treatment options & what’s new
    • How to use treatments
    • Treatment – emerging side effects
    • Osteoporosis & the receiving physician
    Osteoporosis & fracture risk reduction
  • 89. ONJ - BONJ First reported 2003, now 500+ cases Risk in osteoporosis with oral BPs 1:10,000 to <1:100,000 patient-treatment yr Risk in cancer with high dose IV BPs 1:10 to 1:100 patient-treatment yr But true incidence maybe higher!! Khosla et al JBMR 2007:22:1479-1491 Migliorati 2003; Marx 2003; Ruggiero et al 2004
  • 90. Atypical ‘simple with thick cortices pattern’ of femoral diaphyseal fractures associated with ALN
    • 1. Simple transverse pattern
    • 2. Beaking of cortex on one side
    • 3. Hypertrophied diaphyseal cortices
    • 4. Results from minimal or no trauma
    Lenart et al NEJM 2008; 358: 1304-6
  • 91.  
  • 92. BPs & Oesophageal Ca Allan Drummond
  • 93. ?oesophageal ca
  • 94.
    • Exposure to Oral Bisphosphonates and Risk of Esophageal Cancer
    • Chris R. Cardwell, PhD; Christian C. Abnet, PhD; Marie M. Cantwell, PhD; Liam J. Murray, MD
    • JAMA.  2010;304(6):657-663. doi:10.1001/jama.2010.1098
    • Oral bisphosphonates and oesophageal cancer
    • Diane K Wyskowski, epidemiologist
    • BMJ 2010;341:c4506
  • 95.
    • Multiple case reports – suggesting multiple types of oesophageal injury
    • Number of studies suggested possible link to oesophageal ca – inadequate methods for definitive link
    • Green study – similar to JAMA paper but suggested > risk oesophageal ca with > prescriptions (longer f/u)
    • Most recently – JAMA paper
    • (note neither study validated diagnoses by medical records or looked at whether drugs taken correctly)
  • 96.
    • Data from UK GP research database 96-06
    • Bisphosphonate & control cohorts
    • Main outcomes – oesophageal/gastric ca
    • Approx 4½ year mean follow-up
    • 41,000 per cohort
    • 0.48/1000 bis, 0.44/1000 control
    • Statistically no significant increased risk
  • 97.
    • Evidence inconclusive proving link between bisphosphonates and oesophageal ca
    • Clear instructions due to known risks eg oesophagitis/ulcers
    • Check for any previous swallowing problems and report any new problems early
    • Should still prescribe with caution
    • Weigh up risk/benefit ratio
  • 98. UK GP Research Database 2954 women & men >40yr with oesophageal cancer Nested case-control study: 5 controls per case Incidence of oesophageal cancer 1+ oral BP prescriptions v none: RR 1.30 (95% CI: 1.02 to 1.66) !0+ prescriptions v none: RR 1.93 (1.37 t o 2.70) Use oral BP >3yr (av ~5yr) v none RR 2.24 (1.47 to 3.43) Green et al. BMJ: 2010; 341: c4444
  • 99. Risk of oesophageal cancer increased with 10+ prescriptions of oral BPs over ~ 5yr period Incidence of oesophageal ca age 60-79: ~1 per 1000 / 5yr Incidence with 5yrs’ oral BPs: ~2 per 1000 / 5yr Green et al. BMJ: 2010; 341: c4444
  • 100. UK GP Research Database 41826 BP users & 41826 controls: Cohort study: 1 control per case Risk of oesophageal cancer Any BP use v none: HR 1.07 (95% CI: 0.77 to 1.49) >3yrs’ BP use v none: HR 1.01 (0.44 to 2.12) Cardwell et al JAMA 2010; 304: 657-663
  • 101. Association between oral BPs & oesophageal ca risk seen in only 1 study Causal link between oral BP & oesophageal ca is not proven More data required Differences in studies: BMJ paper – longer oral BP use Risk versus benefit discussion warranted High risk groups for oesophageal cancers can be identified Awareness of warning symptoms
  • 102. Meta-analysis: 15 trials 5 with patient-level data (n=8151, f/u over 3.6yr) 11 with trial-level data (n=11,921, f/u over 4yr) Incidence of MI in 5 studies with patient-level data HR 1.31 (1.02 to 1.67) in 11 studies with patient-level data HR 1.27 (1.01 to 1.59) Bolland et al. BMJ: 2010; 341: c3691
  • 103. Doesn’t apply to calcium PLUS vitamin D 7+ trials – didn’t consider CVSRFs e.g weight, smoking, HBP, diabetes, IHD & lipid disorders No dose-relationship seen
  • 104.
    • 51yr Male, JA
    • Ex-policeman, now drug enforcement agency
    • 13 th Nov – fell over with motorbike, sustained back pain (lumbar to lower thoracic spine)
    • Persistent ache since, with pain upto 5/10
  • 105.  
  • 106.  
  • 107. Spine X-ray report
    • Generalised osteopaenia
    • LV1, TV12, TV5 & TV6 – grade 3 wedge fx
  • 108.
    • PMH: Back pain since 1987 – noted to have VFx at LV1 assoc with RTA
    • ~1997, another back injury assoc with RTA & noted to have VFx at TV3 & TV4
    • Mild oesophagitis 1992
    • DU 1993
  • 109.
    • Rx: Venlafaxine
    • NSAID
    • Diazepam
    • SH: lives with wife & 2 children
    • Non-smoker
    • 8U alcohol / w
    • Dietary Ca2+: ≥ 1000mg/d
    • Exercise – daily yoga or swimming
    • RF: Paternal hip fx age 83yr
    • Mother acq’d kyphosis with aging
    • - associated height loss of 6ins
    • - confirmed osteoporosis
  • 110.
    • O/E: Spine configuration – normal
    • Range movements – sl.  all directions
    • No focal tenderness
  • 111.  
  • 112.  
  • 113.  
  • 114.
    • ‘ Radiological osteopaenia’
      • plain X-rays not sensitive for bone loss
      • the need for DXA?
    • When osteoporosis confirmed at young age
      • careful hx essential
      • circumstances of fx
      • growth & development
      • systematic hx – gi, renal, haem, endo,
      • Rx
      • FH
  • 115.
    • What examination is essential?
    • exclude Cushing’s syndrome
    • assess for hypogonadism – incl testicles, gynaecomastia etc.
    • What tests are necessary?
      • Precautions re timing
  • 116. The Clinical Problem Osteoporosis - under-recognized in men, & untreated in most men with fractures. 60yr male - 25% risk of osteoporotic fx during lifetime Nguyen et al. Am J Epidem 1996; 144: 255-63 1/3 of all hip fractures occur in men Gullberg et al. Osteoporos Int 1997;7:407-413. Mortality after hip, vertebral & other fx is higher in men Center et al. Lancet 1999; 353: 878 After hip fracture 4.5% men v 49.5% women undergo assessment or receive antiresorptive Rx Kiebzak et al Arch Int Med 2002; 162: 2217
  • 117. Mortality After All Major Types of Osteoporotic Fracture in Men & Women: An Observational Study Center et al Lancet 1999; 353: 878-882 Mortality Rates for Fracture Patients v General Population
  • 118.
    • The Clinical Problem – Diagnosis
      • WHO thresholds for diagnosis of osteoporosis & osteopaenia in postmen. women, also apply to men.
      • For any given spine or hip BMD, risk of fracture is
      • similar among men & women of the same age.
      • But men with hip fracture have higher BMD than women, (? other factors e.g. microarchitecture or trauma, may contribute more to risk of fracture in men
      • For diagnostic purposes, sex-specific T score is used
    • EPOS. J Bone Miner Res 2002;17:2214-2221.
    • de Laet et al J Bone Miner Res 2002;17:2231-2236. 
    • Johnell et al Calcif Tissue Int 2001;69:182-184. 
  • 119. Spine & hip BMD & T- scores in men & women with NVFx  0.0001 -1.6 (1.23) -1.29 (1.09) T-score  0.0001 0.706 (0.159) 0.798 (0.174) BMD(g/cm 2 ) Total hip  0.0001 -1.94 (1.38) -1.54 (1.45) T-score  0.0001 0.834 (0.152) 0.921 (0.16) BMD(g/cm 2 ) Spine (L1-4)  0.0001 68.2 (10.3) 65.2 (10) Age p Female Male
  • 120. FLS: Prevalence of Osteoporosis in Men with Fractures (all sites) Sharma,S., Fraser, M., Lovell, F., Reece, A., McLellan A.R. JBJS 2008;90: 72-7 n 344 369 310 289 295 234 139 75
  • 121. Prevalence of Osteoporosis in Women & Men with Fractures Sharma,S., Fraser, M., Lovell, F., Reece, A., McLellan A.R. JBJS 2008;90: 72-7 %
  • 122. 60% have secondary osteoporosis 15% 85%
  • 123.
    • The Clinical Problem - Hypogonadism
    • in 66% of elderly male nursing-home residents with hip fractures.
    • in 20% of men with spinal fractures
    • in most cases - asymptomatic
    Abbasi et al. Am J Med Sci 1995;310:229-234
  • 124. Labs JA, 51yr M
    • U&Es, LFTs, TFTs – all normal
    • Adj Ca2+ 2.41mmol/L, ALP 94U/L
    • LH 2.4U/L, FSH 4.5U/L
    • Testosterone 12.1(range 10-36)
    • SHBG 65nmol/L
    • Free testo 151pmol/L (range >200)
    • TTG
    • IGS & EP
  • 125.  
  • 126. Prevalence of the major risk factors for osteoporosis & for fracture
  • 127. Efficacy of Rx in Men (DBRPCTs) Orwoll et al NEJM 2000; 343: 604 n=241, VFx 0.85 (ALN) v 7% (PBO), p0.02 Boonen et al JBMR 2009; 24: 719 n=284 Lyles et al NEJM 2007; 357: 1799 n=508 men of 2175 Orwoll et al JBMR 2003; 18: 9 n=437, 11mo f/u only ND ND ND TESTO ND ND ND 1-34PTH ND ? ? ZOL ND ND ND RIS ND ND Yes ALN Hip Fx Non-VFx VFx Rx
  • 128. Alendronate for the Treatment of Osteoporosis in Men Orwoll et al. NEJM 2000; 343: 604-610 Double-blind placebo controlled RCT over 2yr 241 men; 31-87yr, average age 63yr FN T-score  -2 + LS T-score  -1 or FN T-score  -1 +  1 vertebral deformity or hx of osteoporotic fracture Alendronate 10mg/d + 500mg Ca/d + 400IU vitD/d OR PBO + 500mg Ca/d + 400IU vitD/d
  • 129. Alendronate for the Treatment of Osteoporosis in Men Orwoll et al. NEJM 2000; 343: 604-610 Incidence of morphometric vertebral fractures ALN 7.1% PBO 0.8% p=0.02
  • 130. 1 + Vertebral fracture Osteoporosis & fracture risk assessment Fracture secondary prevention as per protocol Check for history of warning symptoms Past history of cancer in last 10 yr Unexplained weight loss Worsening pain associated with VFx over last 3 months Blood tests ESR , FBC , U & Es , LFTs , Ca , PO 4 , IGS & EP , vitD , TFTs & in males - testo , LH / FSH WARNING SYMPTOMS or SIGNIFICANT ABN BLOODS ? Yes No Other tests If male - PSA If past bowel ca – CEA If past ovarian ca – CA 125 CXR ( if not done in last 3 / 12 ) MRI / CT spine if appropriate to excl tumour If strongly suspect neoplasm or if otherwise unwell or Severe pain / pain management problem Yes No Urgent admission E 3 / 4 Urgent new Bone Clinic appointment 2 - 4 weeks DADS follow - up @ 2 yr incl morphometry IF PAIN – ENSURE OPTIMAL PAIN MANAGEMENT How many vertebral fractures are present ? 3 + 1 - 2
  • 131.