Training Course in Sexual and Reproductive Health Research Geneva, February 17 2009 Osteoporosis Prof René Rizzoli M.D. Division of bone diseases WHO collaborating center for osteoporosis prevention Department of rehabilitation and geriatrics Geneva university hospitals and Faculty of medicine Geneva, Switzerland
Osteoporosis Definition A systemic skeletal disease characterized by low bone mass and microarchitectural deterioration, with a consequent increase in bone fragility with susceptibility to fracture. Consensus Development Conference: Am J Med 1991;90:107-110
Osteoporosis: a 2-Stage Disease With Without Fracture
Osteoporosis: Lecture Content Disease Definition Epidemiology Burden Diagnosis Pathophysiology Management
Fractures by Age and Gender Dubbo Osteoporosis Epidemiology Study, 1989 1994 30 25 20 Minor Fractures Other Major Fractures Vertebral Fractures Proximal Femur Fractures 15 10 5 0 Center J et al. Lancet. 1999;353:878 882. Women Men Women Men Women Men 60 69 70 79 > 80 Age Group (Years)
Lifetime risk of fragility fracture in the Swedish population at the age of 50 years (%) Women Men Proximal femur 23 11 Distal forearm 21 5 Vertebral (clinical) 15 8 Proximal Humerus 13 5 Any 46 % 22 % (Switzerland 51 % 20 %) From Kanis et al 2000
Annual incidence x 1000 Osteoporotic Fractures in Women: Comparison With Other Diseases 2000 1500 1000 500 1 500 000 * 250 000 hip 250 000 forearm 250 000 other sites 750 000 vertebral 513 000 * annual incidence all ages annual estimate women 29+ annual estimate women 30+ 1996 new cases,all ages 228 000 184 300 0 Osteoporotic Fractures Heart Attack Stroke Breast Cancer Riggs BL, Melton LJ. Bone. 1995. Heart and Stroke Facts. 1996. American Heart Association. Cancer Facts & Figures. 1996. American Cancer Society.
Projected burden of osteoporotic 3250 hip fractures worldwide 800 600 400 Estimated n of hip Fractures (1000s) 1950 2050 200 0 North America Europe Latin America Asia Number of hip fractures: 1990: 1.66 million; 2050: 6.26 million Adapted from Cooper C., Melton U, Osteoporosis Int 2:285-289, 1992
If the prevalence of hip fracture continues to rise at current rates, it may well be that in the next few decades, orthopaedists will do little else but treat this problem. W. C. Hayes, In: Bone Formation and Repair (American Academy of Orthopaedic Surgeons) 1994
Burden
Degree of dependence Hip fracture Vertebral fracture Forearm fracture normal aging 50 60 70 80 90 Age (years)
Morbidity After Vertebral Fractures Back pain Loss of height Deformity (kyphosis, protuberant abdomen) Reduced pulmonary function Diminished quality of life: loss of self-esteem, distorted body image, dependence on narcotic analgesics, sleep disorder, depression, loss of independence
A Fragility Fracture -> Fracture
A dangerous vicious circle Low bone mass Social isolation New fracture Depression Loss of autonomy Pain First fracture Inactivity
Mortality after Major Types of Osteoporotic Fracture in Men and Women: an Observational Study Center et al, Lancet 1999 5 - Year Prospective Cohort Study Age-Standardized Mortality Ratio Fracture Women Men Proximal Femur 2.2 3.2 Vertebral 1.7 2.4 Other Major 1.9 2.2 Other Minor 0.8 1.5
Survival probability 1.00 Survival after Hip Fracture Trombetti et al, Osteoporos Int 2002 Expected survival in the the general population 0.75 Hip fractured Women Women 0.50 0.25 Hip fractured Men Men 0.00 2 4 6 8 10 Time after hip fracture (years)
Disability-Adjusted Life-Years Lost because of Non-communicable Diseases in Europe Osteoporosis Ischemic Heart Diseases Chronic Obstructive Pulmonary Diseases Osteoarthritis Alzheimer s Cirrhosis Asthma Migraine Hypertensive Heart Disease Rheumatoid Arthritis Peptic Ulcer Parkinson s Multiple Sclerosis Benign Prostatic Hyperplasia Johnell & Kanis, Osteoporos Int 2006 0 1000 2000 3000 4000 Disability-Adjusted Life-Years (DALYs) Lost
Osteoporosis Results in More Cost than Many Other Diseases Number of bed days (men and women) 701,000 for osteoporosis 891,000 for COPD 533,000 for stroke 328,000 for myocardial infarction 201,000 for breast cancer Osteoporosis # 1 when looking at women only Lippuner et al. Osteoporosis Int 1997; 7: 414-25
Diagnosis
pdxa X-ray techniques pqct DXA
DXA: Principle Two attenuation profiles: Low energy X-ray attenuation High energy X-ray attenuation I o Multiply high energy profile by k factor (ratio of soft tissue attenuation at low- & high-energy) I BMD along scan = Low-energy profile - k-corrected high energy profile
Relative risk 12 Gradients of risk 10 8 6 4 BMD & Hip fracture BP & stroke Cholesterol & MI 2 0 I II III IV Quartile
Noninvasive Measurement of Bone Mineral Mass Technique Site Precision Cost Response to Therapy SXA Forearm ++ ± ± Heel DXA Spine ++ + ++ Hip + + + Tot. Body ++ + ± QCT Spine ± ++ + Forearm ++ +(+) ± US Heel ± - - + Fingers
JAMA 288:1889-1897,2002 Medicare Coverage for BMD Tests Procedure Site Fee Schedule Medicare * DXA Axial $ 128 pdxa Appendicular $ 40 RX Absorptiometry Appendicular $ 38 QUS Appendicular $ 53 SXA Appendicular $ 40 QCT Axial $ 185 pqct Appendicular $ 40 * Medicare Allowable Charge = 80% of the Costs
Example for T-score = - 2.0, 60 year old and Z-Score = - 0.5 1.32 Spine: L1-L4 T-Score +1 BMD g/cm 2 1.20 1.08 0.96 0.84 T Z 0-1 -2-3 0.72-4 20 40 60 80 100 Age
Diagnosis of Osteoporosis Using Central DXA WHO-Definition Normal -1 T-score Osteopenia < -1 and > -2.5 Osteoporosis -2.5 Severe Osteoporosis -2.5 with Fracture Mainly for Spine and Hip in Women
Pathophysiology
Osteoporosis Pathogenesis and Management Fracture Fracture Treatment Rehabilitation -> To Restore Independence -> To Reduce Disabilities Prevention Subsequent Fracture
Osteoporosis Pathogenesis and Management Osteoporosis Low Peak Bone Mass Sex Hormone Deficiency Age Nutritional Insufficiency Mechanical Incompetence Fracture Fracture Treatment Rehabilitation -> To Restore Independence -> To Reduce Disabilities Prevention Subsequent Fracture
Osteoporosis Pathogenesis and Management Falls Sway Walking Muscle Strength Neuro-muscular Impairment Mechanical Overload Osteoporosis Low Peak Bone Mass Sex Hormone Deficiency Age Nutritional Insufficiency Mechanical Incompetence Fracture Fracture Treatment Rehabilitation -> To Restore Independence -> To Reduce Disabilities Prevention Subsequent Fracture
Determinants of Fracture Risk 1.Age 2. Prevalent Fracture 3. Family history of Fracture 4. Glucocorticoid 5. Low BMI 6. Alkohol, Smoking 7. Baseline BMD 8. Baseline Turnover
Type I collagen epitopes and Cathepsin K cleavage sites NTX ICTP CTX CK CK CK CK a2 (I) JYDGKGVG GPP-SAGFDFSFLPQPPQ EKAHDGGR a 1 N C CK Deoxypyridinoline Pyridinolines CK Garnero et al., JBC, 1998 Sassi et al., Bone, 2000
Bone Mineral Mass Tracking of Bone Mineral Mass Fracture Risk A B 10 20 Age (years) 50 90
Age: 10 20 40 70 Rizzoli et al.,j Mol Endocrinol 2001
Heredity Gender Mechanical Forces Peak Bone Mass Hormones Risk Factors Nutrition
Resorption Reversal Resting Formation
Coupled and balanced Coupled but imbalanced Uncoupled but balanced Uncoupled and imbalanced
MALNUTRITION IN ELDERLY Calcium Deficiency Vitamin D Deficiency - > PTH - > Bone Resorption OSTEOPOROSIS - > IGF-1 Protein Deficiency - > Bone Formation - > Sensitivity to IGF-1
Management Indication to treatment Treatment possibilities
Subjects Number Osteoporosis Preventive Strategies Present Situation Higher Risk Population Modfication Whole Population Modification Target very High Risk 4 3 2 1 0 1 2 3 BMD (SD units)
Probability of osteoporotic fracture* at age 65 Men Women 10-year probability (%) 70 60 50 None Prior fracture +Glucocorticoids +Family history 40 30 20 10 0 0-1 -2-3 T-score 0-1 -2-3 US Caucasian, no CRF, BMI=24 *Hip, spine, humerus, forearm
06ca106 FRAX Patient 65-2.5 65 165 24 23.9 8.0
10-Year Risk: 10% 2 20% 30% 40% 1 50% Age
General Management Treatment of any Disease Causing Bone Loss Ensure Dietary Calcium Intake 1000 mg /d Ensure Adequate Dietary Protein Intake Correct or Prevent Vitamin D Insufficiency (800 IU/d) Promote Weight-Bearing Physical Exercise Reduce Falling Risk Reduce Fall Consequences (Hip Protectors)
Risk Factors Associated with Falls 1. Impaired Mobility, Disability 2. Impaired Gait and Balance 3. Neuromuscular or Musculoskeletal Disorders 4. Age 5. Impaired Vision 6. Neurological, Heart Disorders 7. History of Falls 8. Medication 9. Cognitive Impairment After Myers et al., Bone 1996
The Hip Protector Hip Fracture Prevention RCT in Community: No RCT in Nursing Homes: Cluster Random.: Yes Individual Random.: No Left vs Right: No Problems Compliance Persistence
Therapeutic Agents Used in Osteoporosis Anticatabolic Agents Estrogens ± Progestagens SERMs Bisphosphonates Calcitonin Calcium Denosumab Complex Action Vitamin D and Derivatives Anabolic Steroids (Ipriflavone) Tibolone Anabolic Agents (Fluoride) Parathyroid Hormone Mixed Action Strontium Ranelate
Vitamin D and Risk of Falling H. Bischoff-Ferrrari et al JAMA 2004
Hormone Replacement Therapy and Fracture Risk Hip Placebo HRT Vertebral WHI Study, Cauley et al, 2003 All Fractures
Difference % vs. placebo Cardiovascular diseases Stroke Tromb. venous Breast cancer Intestinal cancer Vertebral fracture Hip fracture Women s Health Initiative - First randomized, controlled trial in women (50-79 years) treated with HRT 6700 women with 5.2 years of follow-up 160 120 80 40 0-40 -80 Disadvantages +112% +29% +41% +26% -37% -34% -34% Advantages Manson JE at al, N Engl J Med, 2003;349:523-534
RLX 60 (MORE)* RLX 60 (MORE)** ALN 5/10 (FIT1)* ALN 5/10 (FIT2)** Anti -fracture efficacy (RR ± 95% CI) Vertebral Fx RIS 5 (VERT-NA)* RIS 5 (VERT-MN)* IBAN 2.5 *** IBAN inter ZOL CT 200 (PROOF)* Teriparatide 20µg* Strontium ranelate (SOTI)* Strontium ranelate (SOTI +TROPOS)** 0.2 0.6 1.0 * with prev vert fracture(s) ** without prev vert fractures *** with or without prev vert fractures Update from Delmas 2002
Anti -fracture efficacy (RR ± 95% CI) Vertebral Fx Non-Vertebral Fx RLX 60 (MORE)* RLX 60 (MORE)** RLX 60, 120 (MORE)*** ALN 5/10 (FIT1)* ALN 5/10 (FIT1)* ALN 5/10 (FIT2)** ALN 5/10 (FIT2)** RIS 5 (VERT-NA)* RIS 5 (VERT-MN)* IBAN 2.5 *** IBAN inter ZOL RIS 5 (VERT-NA)* RIS 5 (VERT-MN)* RIS 2.5/5 (Hip Study)*** IBAN ZOL CT 200 (PROOF)* Teriparatide 20µg* Strontium ranelate (SOTI)* Strontium ranelate (SOTI +TROPOS)** 0.2 0.6 1.0 CT 200 (PROOF)* Teriparatide 20µg* Strontium ranelate (SOTI)* Strontium ranelate (TROPOS)*** 0.2 0.6 1.0 * with prev vert fracture(s) ** without prev vert fractures *** with or without prev vert fractures Update from Delmas 2002
Anti -fracture efficacy (RR ± 95% CI) RLX 60, 120 (MORE)*** Hip Fx Significant hip fracture risk Reduction: 3 studies Only studies with preplanned analysis: RIS 2.5/5 (Hip Study) ZOL 5 mg (Horizon Study) ALN 5/10 (FIT1)* ALN 5/10 (FIT2)** RIS 5 (VERT-NA)* RIS 5 (VERT-MN)* RIS 2.5/5 (Hip Study)*** IBAN ZOL CT 200 (PROOF)* Teriparatide 20µg* Strontium ranelate (SOTI)* Strontium ranelate (TROPOS)*** 0.2 0.6 1.0 * with prev vert *** with or without prev vert fractures
Bisphosphonate New Schedules of Administration 1. Weekly (Alendronate, Risedronate) -> Monthly Oral Administration - Ibandronate - Risedronate 2. Trimonthly Intravenous Administration - Ibandronate 3. Annual Intravenous Administration - Zoledronate * 4. Sequential Regimen (PTH -> ALN, RIS or ALN -> PTH) *: Fracture Data
Mechanism of Action of Denosumab Growth Factors Hormones Cytokines Denosumab OPG RANKL RANK CFU-M Pre-Fusion Osteoclast Multinucleated Osteoclast BONE Activated Osteoclast
Incidence (%) Phase III Trial on the Effects of Denosumab on Vertebral Fracture Risk in Women with Postmenopausal Osteoporosis Reduction in vertebral fracture risk 78 % p < 0,0001 65 % p < 0,0001 3,5 3 61 % p < 0,0001 3,1 % 3,1 % Placebo 2,5 2 2,2 % Denosumab 1,5 1 0,9 % 0,7 % 1,1 % 0,5 0 Year 1 0-1 Year 2 1-2 Year 3 2-3 ASBMR 2008 - D après Cummings S.R. et al., San Francisco, États-Unis, abstract 1286,
Cumulative Incidence (%) Cumulative Incidence (%) Phase III Trial on the Effects of Denosumab on Non-Vertebral Fracture Risk in Women with Postmenopausal Osteoporosis Hip Fractures Non-Vertebral Fractures 2,0 1,5 1,0 0,5 Placebo Denosumab Hip Fracture : 69 1,2 % 0,7 % 40 % p = 0,036 IC 95 : 3-63 10 8 6 4 2 Placebo Denosumab 8,0 % No-Vertebral Fractures : 531 20 % p = 0,011 IC 95 : 5-33 6,5 % 0 0 6 12 18 24 30 36 0 0 6 12 18 24 30 36 Months Months ASBMR 2008 - D après Cummings S.R. et al., San Francisco, États-Unis, abstract 1286,
Osteoporosis Treatment in 2009 Summary HRT: spine fx; hip fx SERMS: spine fx; no effect on peripheral fx Calcitonin: possible spine fx; no hip data Alendronate: spine fx; hip fx Risedronate: spine fx; hip fx Ibandronate: spine fx; no effect on hip Zoledronate: spine fx; hip fx PTH: spine fx Strontium Ranelate: spine fx; hip fx Denosumab: spine fx; hip fx
Adapted from E. Seeman (2004) Factors Influencing Treatment Decision Advancing age Lower BMD Presence of Fracture Risk factors or disease causing continued bone loss Leanness Family history BMD T score - 1.0 SD - 2.5 SD 50 55 60 65 70 75 HRT Lower BMD Treatment No Yes, if fx Yes Increasing need to treat RALOXIFENE Older Normal Osteopenia Osteoporosis 80 BISPHOSPHONATES STRONTIUM RANELATE PTH CALCIUM Vit D (if deficient)
1. Aim of Therapy Treatment of Osteoporosis = Treatment of Patients with Osteoporosis 2. Never Too Late
Fractures are not Unavoidable Expenses to Pay as a Consequence of Increased Life-Expectancy Because of Better Identification of Risk Factors for Osteoporosis Early Diagnosis, before the First Fracture A Larger Use of Preventive and Therapeutical Strategies, whose Efficacy has been Demonstrated in Randomized Controled Trials, with Fracture Incidence as Primary End- Point
Kaplan-Meier (K-M) fracture rate (%) 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 Effect of Bazedoxifene on Vertebral Fracture in Postmenopausal Women with Osteoporosis Incidence of new vertebral fracture (intent-to-treat population 0-36 months) Bazedoxifene 20 mg Bazedoxifene 40 mg Raloxifene 60 mg Placebo * p < 0.05 for any active group versus placebo -0.5 0 6 12 18 24 30 36 42 Months Results * the reduction in the incidence of new vertebral fractures was (as compared to placebo) - 42% in group I - 37% in group II - 42% in group III there was no treatment effect on NVF there was no difference between the different groups with regard to adverse effects Bazedoxifene significantly reduces the risk of new vertebral fracture in postmenopausal women with osteoporosis ASBMR 2007 From Silverman SL et al., Beverly Hills, USA, abstract 1206, updated
Long-Term Vertebral and Non-vertebral FractureRisk Reduction with Strontium Ranelate Favors Strontium ranelate RR Over 5 years - 24% Vertebral fractures P<0.001-15% - 18% Non vertebral fractures Major non vertebral fractures P=0.032 P=0.025-31% Vertebral fractures, 80 years - 26% Non-vertebral fractures, 80 years P=0.010 P=0.019 0 0.5 1 1.5 Reginster et al 2007 RELATIVE RISKS AND 95% CI
Pathogenesis of Osteoporotic Fracture LOW PEAK BONE MASS POSTMENOPAUSAL BONE LOSS AGE-RELATED BONE LOSS LOW BONE MASS Other risk factors Nonskeletal factors (propensity to fall) FRACTURE Poor bone quality (architecture)
Hip Fracture Risk Vitamin D & Calcium Versus Placebo/No Treatment Source Favors Treatment Favors Placebo Weight (%) Relative Risk (95% CI) Chapuy et al. 1994 0.74 (0.60-0.91) 38.9% Dawson-Hughes et al. 1997 Chapuy et al. 2002 Porthouse et al. 2005 RECORD Trial Group 2005 WHI Trial Group, 2006 0.2% 6.5% 2.8% 10.9% 40.7% 0.36 (0.02-8.78) 0.62 (0.36-1.07) 0.71 (0.31-1.64) 1.14 (0.76-1.73) 0.88 (0.72-1.07) Pooled Estimate 100.0% 0.82 (0.71-0.94) 0.1 0.5 1.0 1.5 2.0 Relative Risk (95% CI) of Hip Fracture P=0.0005 Boonen, Lips et al., unpublished observations
Bone Mineral Mass Tracking of Bone Mineral Mass Accrual 10 20 Age (years)