Presentation on theme: "Critical Challenges in Osteoporosis From Patient Presentation To Therapeutic Decision Points: An Overview of Issues, Concepts, and Clinical Strategies."— Presentation transcript:
Critical Challenges in Osteoporosis From Patient Presentation To Therapeutic Decision Points: An Overview of Issues, Concepts, and Clinical Strategies SCREEN AND INTERVENE Evidence-Basis for Patient Screening and Risk Stratification: Principles for Approaching a Broad Population of Patients at Risk for Osteoporosis
Definitions Definitions Epidemiology Epidemiology Pathophysiology Pathophysiology Clinical Features Clinical Features Diagnosis Diagnosis Therapy Therapy Program Contents Program Contents
1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. JAMA. 2001;285:785-795. Definition Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to increased risk of fracture 1
Key Features of Osteoporosis Bone involution in both sexes with aging and a superimposed acceleration of bone loss in women after the menopause Bone involution in both sexes with aging and a superimposed acceleration of bone loss in women after the menopause Low bone mass coupled with micro-architectural deterioration leading to enhanced bone fragility and ultimately fracture Low bone mass coupled with micro-architectural deterioration leading to enhanced bone fragility and ultimately fracture
Contents Epidemiology Epidemiology Prevalence Prevalence Incidence Incidence Sites Sites Cost Cost Status of care Status of care
44 million Americans have or are at risk of osteoporosis 44 million Americans have or are at risk of osteoporosis 55% of all people ages 50 years 55% of all people ages 50 years 10 million have osteoporosis 10 million have osteoporosis 34 million more have low bone mass 34 million more have low bone mass 50% of women aged 50 years will experience a fracture in their lifetime 50% of women aged 50 years will experience a fracture in their lifetime Prevalence is expected to increase with the growth of the elderly population Prevalence is expected to increase with the growth of the elderly population Prevalence
Prevalence of Osteoporosis Will Increase With an Increasing Aging Population Paiement GD, Perrier L. In: Comprehensive Management of Menopause. 1994:32-38. US Census Bureau. 2000. 0 5 10 15 20 % Projected Population >65 Years 1900 1950 1985 2020
Osteoporotic Fracture Incidence Is High 0 200,000 400,000 600,000 800,000 1,000,000 1,200,000 1,400,000 1,600,000 Breast Cancer Heart Disease Osteoporotic Fractures Cases/Year Womens Health Facts and Figures. Washington, DC: ACOG; 2000.
NIH/ORBD National Resource Center. October 2000. Vertebral 46% (700,000) Wrist 16% (250,000) Hip 19% (300,000) Other 19% (300,000) Distribution of Fractures
High Economic Burden Estimated $13.8 billion/year Outpatient ($1.3) Hospitalization ($8.6) NursingHome($3.9) Ray NF et al. J Bone Miner Res. 1997;12:24-35.
3% to 5% of hip fracture patients are diagnosed for osteoporosis and treated 3% to 5% of hip fracture patients are diagnosed for osteoporosis and treated 3% of wrist fracture patients receive BMD testing 3% of wrist fracture patients receive BMD testing Only 12% of vertebral fractures are diagnosed and 2% are treated Only 12% of vertebral fractures are diagnosed and 2% are treated Current Status of Care Freedman KB et al. J Bone Joint Surg Am. 2000;82:1063-1070. Gehlbach SH et al. Osteoporosis Int. 2000;11:577-582. Wiktorowicz ME. J Bone Miner Res. 1997;12:S252.
Pathophysiology Pathophysiology Bone Remodeling Bone Remodeling Types of Osteoporosis Types of Osteoporosis Content
OsteoclastResorptionOsteoblastOsteoblastRecruitmentOsteoidDeposition Mineralization Courtesy: Dr. Mone Zaidi The Bone Remodeling Cycle
High Remodeling Hypogonadal (including post-menopausal) Hyperparathyroidism Hyperthyroidism Others Low Remodeling Involutional (Aging) Glucocorticoids (high dose) HIV Disordered Bone Remodeling as the Cause of Osteoporosis
Pathogenesis of Osteoporoses Resorption Must Exceed Formation Normal Remodeling Osteoclast Overactivity Hypogonadal States Parathyroid and Thyroid Osteoblast Dysfunction Involutional (Aging) GlucocorticoidsHIV Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine
Clinical Features Clinical Features Vertebral Fractures Vertebral Fractures Non-Vertebral Fractures Non-Vertebral Fractures Risk Stratification Risk Stratification Content
Vertebral Fractures Most common fractures (46%) Most common fractures (46%) Insidious Insidious Progressive Progressive Often unrecognized Often unrecognized Associated with Associated with –Deformity, height loss, back pain –Morbidity and mortality Predict future vertebral and non- vertebral fractures Predict future vertebral and non- vertebral fractures
Entire skeleton can be involved Entire skeleton can be involved –Wrist –Ankle –Pelvis –Humerus –Rib –Others Associated with significant disability Associated with significant disability NonVertebral Fractures
Most serious clinical event Most serious clinical event Morbidity is high Morbidity is high –50% do not regain independence –50% do not regain previous mobility Mortality is high Mortality is high –1 in 5 patients die within 1 year Patients not treated for osteoporosis Patients not treated for osteoporosis NIH Consensus Development Panel. JAMA. 2001;285:785-795. Hip Fracture
Low BMD Low BMD Fracture after 50 years Fracture after 50 years Age 65 years Age 65 years Maternal history of fracture after 50 years Maternal history of fracture after 50 years Low body weight ( 125 lb) Low body weight ( 125 lb) Smoking Smoking Corticosteroid use Corticosteroid use Other secondary causes Other secondary causes Black DM et al. Osteoporosis Int. 2001;12:519-528. All postmenopausal women with the following: Risk of Fracture
Klotzbuecher CM et al. J Bone Miner Res. 2000;15:721-739. Future Fractures (Fold Increase) Existing Fracture Wrist Vertebral Hip 1.9 2.3 Vertebral 1.7 4.4 2.5 Wrist 3.3 1.4 - A Fracture Begets a Future Fracture
Fracture Stratification Key Points Main risk factors Main risk factors –Low BMD –Presence of a fracture after 50 years Risk for fracture increases Risk for fracture increases –With number of risk factors –With each subsequent fracture
Diagnosis Diagnosis Clinical Assessment Clinical Assessment Diagnostic Criteria Diagnostic Criteria Bone Densitometry Bone Densitometry Content
History History –Risk factor assessment –Medical history –Family history –Social history (smoking, alcohol) –Evaluation of fall risk Physical Physical –Height loss >1.5 inches –Kyphosis Tests Tests –BMD –X-ray of thoracic/lumbar spine –Bone turnover markers –Laboratory tests as necessary AACE Guidelines. Endocr Pract. 2001;7:293-312. Clinical Evaluation
The Kyphotic Woman Likely has osteoporosis and vertebral fractures Confirmatory spinal x-ray for diagnosis Baseline BMD The Non-Kyphotic Woman Spinal x-ray or DXA if height loss >1.5 inches Spinal x-ray or DXA if height loss >1.5 inches Atraumatic vertebral fractures = osteoporosis a Atraumatic vertebral fractures = osteoporosis a Kyphotic vs. Non-Kyphotic
T-Score* Classification > -1.0 Normal -1.0 to -2.5Osteopenia < -2.5 or lowerOsteoporosis < -2.5 + fracture Severe osteoporosis WHO Diagnostic Criteria The WHO Study Group. Geneva, 1994 * T-score = number of standard deviations (SDs) below or above the peak bone mass in young adults.
Risk Assessment/ Research Peripheral DXA (pDXA) Peripheral DXA (pDXA) Ultrasound Ultrasound Quantitative computed Quantitative computed tomography (QCT) tomography (QCT) Diagnosis Central dual energy x- ray absorptiometry (DXA) Gold standard WHO criteria applied National Osteoporosis Foundation. Washington, DC; 1999. Techniques
Central DXA Establish or confirm diagnosis Establish or confirm diagnosis Assess fracture risk Assess fracture risk Follow up Follow up Enhance patient compliance Enhance patient compliance Peripheral DXA Different from WHO T-score criteria Different from WHO T-score criteria Fracture risk assessment in elderly with low T-scores Fracture risk assessment in elderly with low T-scores Central vs Peripheral DXA
Fracture prevention Fracture prevention Stabilize or increase bone mass Stabilize or increase bone mass Provide tolerability and long- term safety Provide tolerability and long- term safety Ensure compliance and adherence Ensure compliance and adherence Goals for Therapy
Calcium intake Calcium intake –Diet and/or supplementation: 1200 mg/day Vitamin D supplementation Vitamin D supplementation –Diagnose and treat deficiency/insufficiency –Supplement: 400-800 IU/day Regular load-bearing and muscle- strengthening exercise (no weight lifting if BMD in spine is low) Regular load-bearing and muscle- strengthening exercise (no weight lifting if BMD in spine is low) Fall prevention advice Fall prevention advice Home safety evaluation Home safety evaluation Nonpharmacologic Approaches
Anti-Resorptive Versus Anabolic High Turnover Bone Loss Low Turnover Bone Loss Anti-Resorptive PTH - Anabolic Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine
Mode of Delivery = Bone Activity Intermittent versus Continuous = Osteoblastic versus Osteoclastic = Formation versus Resorption = Bone Gain versus Bone Loss PTH Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine
PTH – Anabolic Action Receptor Binding and Signal Transduction Enhanced Osteoblast Differentiation Increased Osteoblast Survival Net Increase in Number and Activity of Bone-Forming Osteoblasts
Calcitonin Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine
PROOF: Three Year Analysis Nasal Calcitonin: Efficacy at the Spine and Hip
Estrogen and Raloxifene Reduce the birth (genesis) of new osteoclasts from bone marrow Reduce the birth (genesis) of new osteoclasts from bone marrow Does not inhibit the activity of mature resorbing osteoclasts Does not inhibit the activity of mature resorbing osteoclasts Osteoclast birth increases exponentially to a peak within the first few years of the menopausal transition Osteoclast birth increases exponentially to a peak within the first few years of the menopausal transition Maximum bio-efficacy in early menopause and declines with age and disease severity/fractures Maximum bio-efficacy in early menopause and declines with age and disease severity/fractures Zaidi, M., et. al. (2001) Journal of Bone and Mineral Research.
Structure of Bisphosphonates OH OH OH OH R1 R2 O = P – O – P = O OH OH OH OH Bisphosphonate Polyphosphate O = P – C – P = O
Bisphosphonate Mechanism of Action Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine
Possible Causes of Poor Adherence? Disruption to daily routine? (less frequent dosing) Concern about side effects? Osteoporosis eclipsed by other chronic conditions? Lack of positive reinforcement? Complex dosing guidelines? Poor patient education? POOR ADHERENCE
Adherence With Osteoporosis Medications Is Poor Tosteson ANA, et al. Am J Med. 2003;115:209-216. Patients Abandoning Treatment (%) 30 25 20 15 10 5 0 Hormone Replacement Therapy (n=334) Bisphosphonate (n=366) Selective Estrogen Receptor Modulator (n=256) 26% 19%
Siris E, et al. Presented at: Sixth International Symposium on Osteoporosis. April 6-10, 2005; Washington, DC. Long-term Compliance Reduces Fracture Risk % Patients With Fracture 0 2 4 6 8 10 12 14 CompliantNoncompliant (n=3400) (n=3425) * 9.4% 12.6%
Ettinger M, et al. Arthritis Rheum. 2004;50(suppl):S513-S514. Abstract 1325. Data on file (Reference # 161-040), Hoffmann-La Roche Inc., Nutley, NJ 07110. P<0.001 vs daily therapy 10 20 30 40 50 60 70 80 90 100 Oct 2002 NovDecJanFebMarAprMayJunJulAugSepOct 2003 Patients on Therapy (%) Daily Bisphosphonates (n=33,767) Weekly Bisphosphonates (n=177,552) 54.6% 36.9% Daily vs. Weekly Bisphosphonates Has Led To Increased Compliance Daily Weekly
BMD Changes: 30-Minute vs 60-Minute Postdose Fast With Ibandronate-Sodium Tankó LB, et al. Bone. 2003; 32:421-426. 30-minute postdose fast 60-minute postdose fast Although significant vs baseline, the BMD gains seen in the 30-minute postdose fast group were inferior to those seen in the 60-minute postdose group. Spine (L1-L4)TrochanterTotal HipFemoral Neck Mean % Change in BMD (95% Cl) 7 6 5 4 3 2 1 0
The FDA-mandated primary outcome measures (end point) for all pivotal trials is the demonstration of efficacy in reducing vertebral fracture Non-vertebral fractures, BMD and bone remodeling markers are secondary end points Secondary end points are never statistically powered in terms of patient numbers to detect differences between placebo and drug Efficacy Testing Of Anti-osteoporosis Drugs
Multiple non-vertebral sites, the definition of which varies across clinical trials Heterogenous group of bones, with different proportions of cortical and cancellous bone Differences in non-vertebral fracture incidence and disease severity in placebo groups Non-Vertebral Fractures
Conclusions Characterized by a loss of bone mass and architecture Characterized by a loss of bone mass and architecture Inevitable consequence of aging in both sexes Inevitable consequence of aging in both sexes Accelerated following menopause, disease and drugs Accelerated following menopause, disease and drugs Early detection and intervention is mandatory Early detection and intervention is mandatory Fracture stratification allows identification beyond BMD Fracture stratification allows identification beyond BMD Bisphosphonates are the mainstay of therapy Bisphosphonates are the mainstay of therapy Ensuring compliance through less complex dosing should lead to greater therapeutic benefit Ensuring compliance through less complex dosing should lead to greater therapeutic benefit
Fracture Risk Reporting Since the goal of osteoporosis therapy is fracture prevention, patient selection is best based on fracture risk Since the goal of osteoporosis therapy is fracture prevention, patient selection is best based on fracture risk T-score alone does not provide a complete assessment of fracture risk T-score alone does not provide a complete assessment of fracture risk Combination of clinical risk factors with BMD may provide a better way of identifying patients for treatment Combination of clinical risk factors with BMD may provide a better way of identifying patients for treatment
Selection of Clinical Risk Factors Independent of BMD (if BMD is known) Independent of BMD (if BMD is known) Validated in multiple populations (sex, ethnicity, country) Validated in multiple populations (sex, ethnicity, country) Easily obtainable Easily obtainable Amenable to intended treatment Amenable to intended treatment Intuitive Intuitive Adapted from Kanis JA et al. Osteoporos Int. 2005;16:581-589.
Clinical Risk Factors Femoral neck T-score + Age Age Previous low trauma fracture Previous low trauma fracture Current cigarette smoking Current cigarette smoking Rheumatoid arthritis Rheumatoid arthritis High alcohol intake (> 2 units/day) High alcohol intake (> 2 units/day) Parental history of hip fracture Parental history of hip fracture Prior or current glucocorticoid use Prior or current glucocorticoid use Adapted from Kanis JA et al. Osteoporos Int. 2005;16:581-589.
Intervention Threshold A fracture probability above which it is cost-effective to treat with pharmacological agents A fracture probability above which it is cost-effective to treat with pharmacological agents Based on statistical modeling using many medical, social, and economic assumptions Based on statistical modeling using many medical, social, and economic assumptions