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Long-term Management of Osteoporosis March 25, 2013 Ronald C. Hamdy, MD, FRCP, FACP Professor of Medicine Cecile Cox Quillen Chair of Geriatric Medicine Director, Osteoporosis Center East Tennessee State University R. C. Hamdy - Disclosures Speakers’ bureau Advisory Board Speakers’ bureau Speakers’ bureau Speakers’ bureau Long-term Management of Osteoporosis March 25, 2013 OBJECTIVES Evaluate the risk/benefit of long-term therapy for osteoporosis Develop a long-term management strategy tailored to the individual circumstances of the patient. Recognize the possible long-term complications of medications commonly used for osteoporosis Mrs. DA, 68 years old WW - Osteoporosis On alendronate for about 12 years Taking the medication as directed Pain in left thigh, 6 weeks: 6/10 not constant, gradually worse precipitated by exertion, especially jogging partly relieved by rest & local heat now, often wakes her at night. Starting to interfere with daily activities Mrs. DA, 68 years old WW - Osteoporosis On alendronate for about 12 years 12 years ago: T-score -2.9 lumbar vertebrae Surgical menopause at age 32, no HRT Family history: positive, mother fragility hip fracture Good dietary calcium and vitamin D intake Physically active lifestyle, exercises regularly: daily jogging, twice weekly: aerobic/resistive exercises Medication: alendronate calcium/vitamin D supplements Mrs. DA, 68 years old WW - Osteoporosis On alendronate for about 12 years Weight 152 pounds, steady; height 64” No kyphosis Tenderness to deep palpation upper 1/3 left femur Pain worse when she stands on left leg Good range of movement both hips No pain on passively moving both hips Leg raising test negative, both sides No evidence of arthritis No evidence of neurologic deficits Mrs. DA, 68 years old WW - Osteoporosis On alendronate for about 12 years Weight 152 pounds, steady; height 64” No kyphosis Tenderness to deep palpation upper 1/3 left femur Pain worse when she stands on left leg Good range of movement both hips No pain on passively moving both hips Leg raising test negative, both sides No evidence of arthritis No evidence of neurologic deficits Hamdy, RC, Lewiecki, EM. Osteoporosis: Oxford University Press, 2013 Warning sign: Impending fracture Hamdy, RC, Lewiecki, EM. Osteoporosis: Oxford University Press, 2013 Prevention is better than cure Hamdy, RC, Lewiecki, EM. Osteoporosis: Oxford University Press, 2013 Rod inserted prophylactically Hamdy, RC, Lewiecki, EM. Osteoporosis: Oxford University Press, 2013 Reports of femoral shaft fractures occurring in patients on bisphosphonate therapy. Atypical femoral shaft fractures Reports of femoral shaft fractures occurring in patients on bisphosphonate therapy. Femoral Shaft Fractures Fractures occurring anywhere between the lesser trochanter and the supracondylar flare. Femoral Shaft Fractures 7 to 10% of all femoral shaft fractures Bimodal age distribution Femoral Shaft Fractures 7 to 10% of all femoral shaft fractures Bimodal age distribution 75% due to severe trauma • Usually good prognosis Femoral Shaft Fractures 7 to 10% of all femoral shaft fractures Bimodal age distribution 75% due to severe trauma • Usually good prognosis 25% due to low trauma or no trauma Femoral Shaft Fractures 7 to 10% of all femoral shaft fractures Bimodal age distribution 75% due to severe trauma • Usually good prognosis 25% due to low trauma or no trauma • Osteoporosis • More frequent in women than men • Poor prognosis • Mortality: 14% first year, 25% second year • 50% do not achieve pre-fracture level • 71% need alternative accommodation Femoral Shaft Fractures 7 to 10% of all femoral shaft fractures Bimodal age distribution 75% due to severe trauma • Usually good prognosis 25% due to low trauma or no trauma • Osteoporosis • More frequent in women than men • Poor prognosis • Mortality: 14% first year, 25% second year • 50% do not achieve pre-fracture level • 71% need alternative accommodation Femoral Shaft Fractures Typical: underlying osteoporosis v/s Atypical: osteoporosis treatment Atypical Femoral Shaft Fractures ASBMR Task Force - Major Features • No/minimal trauma Between lesser trochanter & supracondylar flare Non-comminuted Medial spike • Unilateral or bilateral • Complete or incomplete Prodromal symptoms • Localized pain • Localized bone tenderness Short transverse or oblique configuration Shane E, et al. JBMR 2010;25:2267‐2294 Atypical Femoral Shaft Fractures ASBMR Task Force • Imaging studies • Insufficiency/stress fractures • Localized periosteal reaction • Localized increased Technetium uptake • Other morbidities Shane E, et al. JBMR 2010;25:2267-2294 Hamdy, RC, Lewiecki, EM. Osteoporosis: Oxford University Press, 2013 Basic Science Considerations Bisphosphonates Prevent Bone Loss Increase Bone Mass Reduced Fracture Risk Reduced Bone Resorption Basic Science Considerations Bisphosphonates Prevent Bone Loss Increase Bone Mass Reduced Bone Resorption Increased Mature Cross-Links Micro-damage AGE Products Reduced Fracture Risk Basic Science Considerations Bisphosphonates Prevent Bone Loss Increase Bone Mass Reduced Bone Resorption Increased Mature Cross-Links Micro-damage AGE Products Reduced Fracture Risk Micro-architectural Deterioration Basic Science Considerations Bisphosphonates Prevent Bone Loss Increase Bone Mass Reduced Bone Resorption Increased Mature Cross-Links Micro-damage AGE Products Micro-architectural Deterioration Increased Bone Brittleness Reduced Fracture Risk Basic Science Considerations Bisphosphonates Prevent Bone Loss Increase Bone Mass Reduced Bone Resorption Increased Mature Cross-Links Micro-damage AGE Products Micro-architectural Deterioration Increased Bone Brittleness Reduced Fracture Risk Stress Fractures Basic Science Considerations Bisphosphonates Prevent Bone Loss Increase Bone Mass Reduced Bone Resorption Increased Mature Cross-Links Micro-damage AGE Products Micro-architectural Deterioration Increased Bone Brittleness Reduced Fracture Risk Stress Fractures Atypical Femoral Shaft Fractures Basic Science Considerations Bisphosphonates Prevent Bone Loss Increase Bone Mass Reduced Bone Resorption Increased Mature Cross-Links Micro-damage AGE Products Micro-architectural Deterioration Increased Bone Brittleness Reduced Fracture Risk Impaired Healing Process Stress Fractures Atypical Femoral Shaft Fractures Basic Science Considerations Bisphosphonates Prevent Bone Loss Increase Bone Mass Reduced Bone Resorption Increased Mature Cross-Links Micro-damage AGE Products Micro-architectural Deterioration Increased Bone Brittleness Reduced Fracture Risk Reduced Bone Angiogenesis Impaired Healing Process Stress Fractures Atypical Femoral Shaft Fractures Atypical Femoral Shaft Fractures Bisphosphonate Therapy Bisphosphonates: 2004: 57 million prescriptions in USA 2007: 225 million prescriptions worldwide Largest case series of Atypical Femoral Shaft Fractures: 320: Shane et al, 2010 141: Giusti et al, 2010 Placebo-controlled Studies Double-blind, randomized, prospective studies Alendronate Risedronate Ibandronate Zoledronic acid Denosumab 2,027 5,445 + 2,458 + 1,116 2,946 7,736 7,736 Extension studies No increased risk Re-analysis of data including extension studies No increased risk* *Black DM et al. NEJM 2010;362(19):1761-71 Retrospective Population Studies Danish registry-based cohort study: 11,944 subjects > 60 years 2-matched cohorts: • 5,187 • 10,374 Patients with FSF were not more likely than patients with hip fractures to be on alendronate, but more patients were on corticosteroids. Abrahamsen B, et al. JBMR 2009;24:1095-1102 Retrospective Population Studies Positive effect of bisphosphonates on FSF Higher reduction of FSF in patients highly compliant with bisphosphonate therapy. • Abrahamsen B, et al. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. JBMR 2009; 24(6):1095-102. • Hsiao FY, et al. Hip and subtrochanteric or diaphyseal femoral fractures in alendronate users: a 10-year, nationwide retrospective cohort study in Taiwanese women. Clin Ther. 2011;33(11):1659-67. ASBMR Task Force Atypical Femoral Shaft Fractures & Anti-resorptive Therapy A causal relationship between bisphosphonates and femoral shaft fractures could not be established. ASBMR Task Force. JBMR 2010;25:2267-2294 Atypical Femoral Shaft Fractures & Anti-resorptive Therapy Over-use, or over-dose not adverse effect Atypical Femoral Shaft Fractures & Anti-resorptive Therapy Over-use, or over-dose not adverse effect Often can be anticipated Femoral Fractures per 100,000 National Hospital Discharge Survey & MarketScan® 1996-2006 Nieves JW, et al Osteoporos Int 2010;21(3):399-408 Femoral Fractures per 100,000 National Hospital Discharge Survey & MarketScan® 1996-2006 Let’s be vigilant, but not stop positive effects of therapy Nieves JW, et al Osteoporos Int 2010;21(3):399-408 Mrs. BD, 68 years old WW - Osteoporosis T-score -2.7, left femoral neck Post surgical menopause at age 34 years, no HRT Positive family history: mother fragility hip fracture Good daily calcium and vitamin D intake No excessive sodium/caffeine intake Exercises regularly: aerobic/resistive exercises No medications No secondary causes Mrs. BD, 68 years old WW - Osteoporosis Refuses bisphosphonates Concerned about atypical femoral shaft fractures Mrs. BD, 68 years old WW - Osteoporosis Refuses bisphosphonates Concerned about atypical femoral shaft fractures Probability of sustaining: Atypical femoral shaft fracture 1:10,000 to 1:20,000 Mrs. BD, 68 years old WW - Osteoporosis Refuses bisphosphonates Concerned about atypical femoral shaft fractures Probability of sustaining: Atypical femoral shaft fracture 1:10,000 to 1:20,000 Osteoporotic fracture Hip # 33% 1:3 Other # 50% 1:2 Mrs. OJ, 68 years old WW - Osteoporosis Has been on oral bisphosphonates for about 12 years Taking them as directed, no adverse effects Dentist concerned about impending tooth extraction Mrs. OJ, 68 years old WW - Osteoporosis Natural menopause at age 47 years, no HRT Positive family history: mother fragility hip fracture Daily dietary calcium intake about 1,200 mg No excessive sodium/caffeine intake Exercises regularly: aerobic/resistive exercises No medications, except alendronate Mrs. OJ, 68 years old WW - Osteoporosis Should bisphosphonates be discontinued? What else can be done to prevent Osteonecrosis of the jaw? Tooth to be extracted Cavity left after tooth extraction Necrotic tissue removed, Larger cavity left, lined by injured bone Some of injured bone: recovers Undergoes necrosis Osteonecrosis of the jaw Tooth to be extracted Cavity lined by injured bone Cavity left after tooth extraction Some of injured bone: recovers Undergoes necrosis Osteonecrosis of the jaw Tooth to be extracted Cavity lined by injured bone Osteoclasts remove injured bone Cavity left after tooth extraction Some of injured bone: recovers Undergoes necrosis Osteonecrosis of the jaw Tooth to be extracted Cavity lined by injured bone Osteoclasts remove injured bone Access denied Cavity left after tooth extraction Some of injured bone: recovers Undergoes necrosis Osteonecrosis of the jaw Tooth to be extracted Cavity lined by injured bone Osteoclasts remove injured bone Cavity left after tooth extraction Some of injured bone recovers Some undergoes necrosis Tooth to be extracted Cavity lined by injured bone Cavity left after tooth extraction Necrotic tissue removed, Larger cavity left, lined by injured bone Some of injured bone: recovers Undergoes necrosis Tooth to be extracted Cavity lined by injured bone Cavity left after tooth extraction Necrotic tissue removed, Larger cavity left, lined by injured bone Some of injured bone: recovers Undergoes necrosis Osteonecrosis of the jaw Mrs. OJ, 68 years old WW - Osteoporosis Stop bisphosphonates/anti-resorptives ?? Effect ?? Ensure no vitamin D deficiency ? Discuss case with dentist If invasive procedure required: experienced oral surgeon/dentist ? Assay bone markers ?? Meticulous oral hygiene Osteonecrosis of the jaw Exposed bone for at least 8 weeks Stage I: Stage II: Stage III: Exposed bone, asymptomatic Infected exposed bone Fistulae, purulent discharge ? Stage 0: Pain in gums in patient on antiresorptive therapy Radiological features Osteonecrosis of the jaw Relatively few cases Mostly in patients: with neoplasia on high doses bisphosphonates on glucocorticoids Other predisposing factors: underlying dental problems cigarette smoking poor dental hygiene Mrs. PRP, WW, 82 years Diagnosed with osteoporosis about 9 years ago Fragility fracture T10: moderate wedge Secondary causes excluded. Started risedronate (Actonel) 35 mg weekly, then converted to 150 mg once a month No adverse effects, taking it as directed, own routine Good compliance Good daily calcium/vitamin D intake Mrs. PRP, WW, 82 years Right Total Hip Scan Date Age BMD T-scores % BMD Change Baseline Previous 2004 73 0.633 - 3.0 2006 75 0.649 - 2.9 + 2.3 + 2.3 2007 2009 76 78 0.682 0.691 -2.8 - 2.7 + 7.7 + 9.2 + 5.1 + 1.3 2011 79 0.704 -2.6 + 11.2 + 1.8 2013 82 0.710 - 2.5 + 12.2 + 0.8 Continue Bisphosphonate ? Mrs. PRP, WW, 82 years Right Total Hip Scan Date Age BMD T-scores % BMD Change Baseline Previous 2003 73 0.633 - 3.0 2005 75 0.649 - 2.9 + 2.3 + 2.3 2006 2008 76 78 0.682 0.691 -2.8 - 2.7 + 7.7 + 9.2 + 5.1 + 1.3 2010 79 0.704 -2.6 + 11.2 + 1.8 2012 82 0.710 - 2.5 + 12.2 + 0.8 Continue Bisphosphonate ? Mrs. PRP, WW, 82 years Right Total Hip Scan Date Age BMD T-scores % BMD Change Baseline Previous 2003 73 0.633 - 3.0 2005 75 0.649 - 2.9 + 2.3 + 2.3 2006 2008 76 78 0.682 0.691 -2.8 - 2.7 + 7.7 + 9.2 + 5.1 + 1.3 2010 79 0.704 -2.6 + 11.2 + 1.8 2012 82 0.710 - 2.5 + 12.2 + 0.8 Continue Bisphosphonate ? Mrs. PRP, WW, 82 years Right Total Hip Scan Date Age BMD T-scores % BMD Change Baseline Previous 2003 73 0.633 - 3.0 2005 75 0.649 - 2.9 + 2.3 + 2.3 2006 2008 76 78 0.682 0.691 -2.8 - 2.7 + 7.7 + 9.2 + 5.1 + 1.3 2010 79 0.704 -2.6 + 11.2 + 1.8 2012 82 0.710 - 2.5 + 12.2 + 0.8 C-TX 320 pg/mL Continue Bisphosphonate Mrs. XEV, WW, 78 years Diagnosed with osteoporosis about 8 years ago Secondary causes excluded. Started oral bisphosphonate weekly, then converted to 150 mg once a month No adverse effects, taking it as directed, own routine Good compliance Good daily calcium/vitamin D intake Mrs. XEV, WW, 78 years Right Total Hip Scan Date Age BMD T-scores % BMD Change 2002 2004 63 65 0.700 0.721 - 2.0 - 1.8 + 3.0 + 3.0 2005 66 0.724 - 1.8 + 3.4 + 0.4 2007 2008 68 69 0.727 0.707 - 1.5 -1.9 + 3.8 + 1.0 + 0.4 - 2.8 2010 72 0.695 - 2.1 - 0.7 - 1.7 Baseline Previous Mrs. XEV, WW, 78 years Right Total Hip Scan Date Age BMD T-scores % BMD Change 2002 2004 63 65 0.700 0.721 - 2.0 - 1.8 + 3.0 + 3.0 2005 66 0.724 - 1.8 + 3.4 + 0.4 2007 2008 68 69 0.727 0.707 - 1.5 -1.9 + 3.8 + 1.0 + 0.4 - 2.8 2010 72 0.695 - 2.1 - 0.7 - 1.7 Baseline Previous Mrs. XEV, WW, 78 years Right Total Hip Scan Date Age BMD T-scores % BMD Change 2002 2004 63 65 0.700 0.721 - 2.0 - 1.8 + 3.0 + 3.0 2005 66 0.724 - 1.8 + 3.4 + 0.4 2007 2008 68 69 0.727 0.707 - 1.5 -1.9 + 3.8 + 1.0 + 0.4 - 2.8 2010 72 0.695 - 2.1 - 0.7 - 1.7 Baseline Previous Mrs. XEV, WW, 78 years Right Total Hip Scan Date Age BMD T-scores % BMD Change 2002 2004 63 65 0.700 0.721 - 2.0 - 1.8 + 3.0 + 3.0 2005 66 0.724 - 1.8 + 3.4 + 0.4 2007 2008 68 69 0.727 0.707 - 1.5 -1.9 + 3.8 + 1.0 + 0.4 - 2.8 2010 72 0.695 - 2.1 - 0.7 - 1.7 Baseline Previous C-Tx 76 pg/mL Mrs. XEV, WW, 78 years Right Total Hip Scan Date Age BMD T-scores % BMD Change 2002 2004 63 65 0.700 0.721 - 2.0 - 1.8 + 3.0 + 3.0 2005 66 0.724 - 1.8 + 3.4 + 0.4 2007 2008 68 69 0.727 0.707 - 1.5 -1.9 + 3.8 + 1.0 + 0.4 - 2.8 2010 72 0.695 - 2.1 - 0.7 - 1.7 Baseline Previous C-Tx 76 pg/mL D/C Bisphosphonate Mrs. WF, 68 yrs, Wt: 140 lbs Ht: 62 in Known to have osteoporosis CBC, Blood Chem. Profile, TSH: within normal limits. Prescribed an oral bisphosphonate. Mrs. WF, 68 yrs, Wt: 140 lbs Ht: 62 in DXA Scan Results Baseline BMD T-score 2 yrs later % Change BMD T-score BMD Right Total Hip 0.721 -2.5 0.689 - 2.9 - 4.5 2.2 Left Total Hip 0.688 -2.7 0.657 - 2.9 - 5.1 2.8 Lumbar Vertebrae Multiple vertebral compression fractures Bisphosphonates, good compliance Complete blood picture Blood chemistry profile Thyroid stimulating hormone Normal LSC Mrs. WF, 68 yrs, Wt: 140 lbs Ht: 62 in DXA Scan Results Baseline BMD T-score 2 yrs later % Change BMD T-score BMD LSC Right Total Hip 0.721 -2.5 0.689 - 2.9 - 4.5 2.2 Left Total Hip 0.688 -2.7 0.657 - 2.9 - 5.1 2.8 Lumbar Vertebrae Multiple vertebral compression fractures Bisphosphonates, good compliance Complete blood picture Blood chemistry profile Thyroid stimulating hormone Normal 25(OH) Vitamin D 12 ng/mL Mrs. RV, 60 years, WW, Second visit RIGHT HIP Fem Neck Total Hip 4-years ago T oday BMD T-score BMD T-score 0.676 - 1.6 0.655 - 1.7 0.688 - 2.1 0.750 - 1.6 % Change BMD - 3.3 - 8.3 LEFT HIP Fem Neck Total Hip 0.609 0.735 - 2.0 - 12.2 L1-L4 Cannot be interpreted: scoliosis and artifacts - 2.2 - 1.7 0.597 0.646 - 2.3 - 2.4 Prescribed alendronate 4-years ago Mrs. RV, 60 years, WW, Second visit RIGHT HIP Fem Neck Total Hip Baseline BMD T-score 0.676 - 1.6 0.750 - 1.6 4 years later BMD T-score 0.655 - 1.7 0.688 - 2.1 % Change BMD - 3.3 - 8.3 LEFT HIP Fem Neck Total Hip 0.609 0.735 0.597 0.646 - 2.0 - 12.2 L1-L4 Cannot be interpreted: scoliosis and artifacts - 2.2 - 1.7 - 2.3 - 2.4 Did not refill her second prescription of Alendronate Non-response to oral bisphosphonates • Compliance/adherence • Inadequate Calcium/vitamin D • Secondary osteoporosis Long-term Management of Osteoporosis March 25, 2013 OBJECTIVES Evaluate the risk/benefit of long-term therapy for osteoporosis Develop a long-term management strategy tailored to the individual circumstances of the patient. Recognize the possible long-term complications of medications commonly used for osteoporosis