What is Osteoporosis?

Transcription

1 What is Osteoporosis? Systemic skeletal disease characterized by: low bone mass (T-score < -2.5) biochemically normal bone microarchitectural deterioration of bone tissue Hallmark- Increased bone fragility and susceptibility to fracture Annual FractureIncidence, per 1, Effect of Age on Fracture Incidence in Women Age (years) Vertebrae Hip Wrist Riggs B. N Engl J Med 1986;314:1676 Healthy Trabecular Bone vs Osteoporotic Bone: 3-D Micro CT 52 year old Female 84 year old Female (w/ vertebral fracture) Prevalence of Low Femoral Neck BMD in U.S. Adults Ages Men Women <- 2.5 SD - 1 to SD Borahet al Anat. Rec.(21) Looker, J Bone Miner Res 1997; 12: Prevalence and Epidemiology of Postmenopausal Osteoporosis (PMO) Factors Leading to Increased Fracture Risk Primarily affects Caucasians and Asians 4-5% of Caucasian women over age 5 are expected to fracture in their remaining lifetime Lower risk exists for Latina and African- American women Lower risk for men (2-3% will fracture)

2 US Economic Burden of PMO Fractures associated with osteoporosis account for: ~ $14-17 billion direct medical costs ($14-17 million KPNC) > 4, hospital admissions ~ 2.5 million physician visits > 18, nursing home admissions Costs of osteoporosis associated fractures by 24: ~ $5 billion Burden of disease hip fracture 4-6 million women in US fracture million in US with low bone density are at risk for hip fracture Men have about 1/3-1/2 this risk Patients(%) Hip Fractures - Associated Morbidity and Mortality 2% Death withinone year Permanent disability 3% Unable to carry out at least one independent activity of daily living Unable to walk independently 4% 8% Prevention of Osteoporosis (Improving Bone Mineral Density) Heredity predicts about 2% Attainment of peak bone density and avoiding bone loss thereafter = skeletal hygiene Calcium intake: 1-12mg in children and adults, 15mg after menopause Weight-bearing exercise Adequate gonadal steroids Avoid smoking and excess EtOH Adequate vitamin D 4 IU in youth, then 8-12 IU Management of Osteoporosis: Prevent first fragility fracture Primary prevention Skeletal hygiene Look for secondary causes of bone loss Fall prevention Medication Secondary prevention Primary prevention + stabilize/increase bone mass medications This is the HEDIS goal to treat with effective meds to prevent further fracturing. Risk Factors for Hip Fracture in White Women from the Study of Osteoporotic Fractures Factor Calcaneal BMD (per 1 SD) Age (per 5 yrs) Hx maternal hip Fracture Any Fracture since age 5 On feet < 4 hr/day Inability to rise from chair Reduced depth perception Current benzodiazepine use Walk for exercise Increase in Risk (%) Cummings et al. NEJM 1995

3 Pathophysiology of PMO: Overview Bone remodeling occurs throughout life to repair microfractures and supply Ca ++ In normal adults, the activity of osteoclasts (bone resorption) is balanced by that of osteoblasts (bone formation) With diminishing estrogen levels (mid-forties or fifties) excessive bone resorption is not fully compensated by an increase in bone formation Bone Remodeling Stable bone maintained by health osteocytes. Activation of resorption Repair microfractures Supply calcium Remodel bone Inflammation Multinucleated giant cells In acidic environment dig pits and recruit osteoblastic formation of osteoid. This is passively mineralized into new bone - hydroxyapatite matrix. Osteocytes maintain bone metabolism. Normal skeletal turnover takes about 2-4 years. Pathophysiology of PMO: Overview Microarchitectural Instability Trabecular bone accounts for most bone turnover Only 25% of the skeletal mass >> 5% bone turnover Vertebrae, distal radius and femoral neck The process is not 1% efficient and there is net loss of bone after the third decade Anything which increases the activity or number of osteoclasts or decreases osteoblasts causes increased bone loss Fractures Increase with Age The steep rise in fracturesamong men occursabout1years laterthan itdoes in women. Bone Gain and Loss Over a Woman s Lifetime Fractures/1,, Person-Years 2,5 5 3, Men 2, Hip 1,5 1, Vertebrae Women Hip Vertebrae -44 > 85 > Age ( years) Adapted from Wasnich, R.D. et al.: Osteoporosis: Critique and Practicum, Honolulu, Banyan Press, 1989, pp Cooper C et al. J Bone Miner Res. 1992; 7:221 Riggs BL et al. NEJM1986;314(26):

4 RelativeBMD (%) BMD and Fracture Risk Are Inversely Related Forearm Spine Hip and Heel Age Annual Fracture Incidence Colles' Vertebrae Hip Age Indications for DXA Scan Women 65+ Men 7+ Adults >55 with Fractures or Risk Factors Other circumstances: Primary hyperparathyroidism Chronic glucocorticoid use Male hypogonadism or androgen deprivation therapy Premature menopause, aromatase inhibitors Prolonged hyperthyroidism DM1 55+ women, 65+ men Monitoring Treatment (Q 3-5 yrs) Faulkner KG. J Clin Densitom. 1998;1: Cooper C. Baillières Clin Rheumatol. 1993;7: Case GR: 67 yr old post menopausal female Off HRT for 6 years Exercises regularly, BP okay on HCTZ 122 #, 5 4, quit smoking 15 yr ago, no h/o Fx Takes calcium and a multivitamin occasionally Mom had a hump but age 84 from CVA BMD? YES! > 65 Bone Density Scans Purpose: 1. Screening for disease 2. Fracture risk assessment 3. Monitor treatment Account for only 6-8% of bone strength. 5% of patients with osteoporotic fracture DO NOT have osteoporotic T scores. Who Has Osteoporosis? Patient Age Fragility fx? T score Who Has Osteoporosis? Patient Age Fragility fx? T score A 84 F N -2.2 A 84 F N -2.2 B 56 F N -2.8 B 56 F N -2.8 C 66 F Y -2.2 C 66 F Y -2.2

5 Risk Factors For Osteoporosis Age History of Fracture Ethnicity Highest risk = Caucasian women Family History Glucocorticoid use 7.5mg prednisone daily for > 3 mo Low BMI Hypogonadism Low estrogen in women, low testosterone in men Risk Factors For Osteoporosis Inadequate calcium and vitamin D intake Immobilization Smoking Heavy alcohol use 3 or more drinks/day Causes of Secondary Osteoporosis Causes of Secondary Osteoporosis Medications Glucocorticoids Antiepileptics Lithium Methotrexate PPI s SSRI s (?) Thiazolidinediones Connective tissue dz Rheumatoid arthritis Ankylosis spondylitis Lupus Nutritional factors Anorexia nervosa Ca ++ intake Vitamin D intake Excess caffeine or alcohol Excess Sodium Lifestyle Smoking Immobilization Excessive exercise Sedentary lifestyle Endocrine causes Hypogonadism Hyperthyroidism Hyperparathyroidism Glucocorticoids Type 1 Diabetes Type 2 Diabetes Hemochromatosis COPD Depression Chronic Renal Failure Pregnancy Malignancy Multiple myeloma Systemic mastocytosis Leukemia GI diseases Liver failure Biliary cirrhosis Inflammatory bowel disease Post gastrectomy, Roux-en-Y or duodenal switch Gluten-sensitive enteropathy (sprue) Most Important Risk Factors for Osteoporotic Fracture 4 Effect of Age on Fracture Incidence in Women Vertebrae 1. Age 2. History of Fracture 3. Everything else. Annual FractureIncidence, per 1, Hip Wrist Age (years) Riggs B. N Engl J Med 1986;314:1676

6 Fracture History = Fracture Risk 2% of patients with vertebral fractures will have another one in the subsequent year. Case GR: 67 yr old post menopausal female Off HRT for 6 years Exercises regularly, BP okay on HCTZ 122 #, 5 4, quit smoking 15 yr ago, no h/o Fx Takes calcium and a multivitamin occasionally Mom had a hump but age 84 from CVA BMD? YES! > 65 Lindsay R, et al., JAMA 21;285(3):32-3. Using FRAX What if she had a fracture? FRAX 1 year fracture risk: Treatment advised With major fracture risk over 2-3% or hip fracture risk over 3-4% Previous Vertebral Fx Predicts Risk of Future Hip Fx % Sustaining a hip Fx Adapted with permission from Melton LJ III, et al. Osteoporosis Int. 1999;1:

7 Who Has The Greatest Fracture Risk? Patient Age Fragility fx? T score 84 y/o with Osteopenia A 84 F N -2.2 B 56 F N -2.8 C 66 F Y y/o with Osteoporosis 65 y/o with T score -2.2 and Fx Who Has The Greatest Fracture Risk? Patient Age Fragility Fx? T score A 84 F N -2.2 B 56 F N -2.8 C 65 F Y yr Fracture Risk Any 17% Hip 5.6% Any 11% Hip 2.7% Any 19% Hip 3.4% Treatment of Osteoporosis = Prevention of Fracture Calcium and Vitamin D Exercise Osteoblast Stimulation Fall Prevention Fall Risk Reduction Minimize Other Risk Factors Tobacco and alcohol Glucocorticoids Hypogonadism Pharmacologic Bisphosphonates PO or IV Estrogen SERM s (Evista) Teriparatide (Forteo) Denosumab (Prolia)

8 Other Factors Calcium Vitamin D Ethnic factors Exercise just do it! Daily Calcium Intake NHANES III All calcium salts are not created equal Elemental Calcium in common products 4 percent of calcium carbonate take after meals: need low ph to dissociate 21 percent of calcium citrate take any time 13 percent of calcium lactate 9 percent of calcium gluconate Aim for mg TOTAL DAILY ELEMENTAL CALCIUM intake Is calcium either necessary or sufficient? Many studies suggest benefit of adequate calcium intake in post-menopausal women Many studies show improved BP and CV outcomes in calcium sufficient populations The safety of calcium supplements (without vitamin D supplements) has been questioned All medication studied include calcium and vitamin D in both placebo and intervention groups Current knowledge: Dietary calcium may be better Supplement deficient patients Supplement patient you are treating for osteoporosis Vitamin D Levels Lower in Higher Latitudes Osteoclastic resorption of bone Serum Ca ++ PTH Ca ++ absorption in gut Renal calcium reabsorption 1,25 dioh vitamin D 25 OH vitamin D 7-deoxycholesterol

9 Vitamin D for Muscle and Bone Health Metabolism and signaling decrease with age. Prevents fall and fractures Vitamin D and PTH 29 consecutive pts. on a general medical ward MGH Multiple studies show fracture prevention with calcium and vitamin D. Negative studies had poor compliance (<6%), inadequate doses (< 8 IU) or 25OH D levels < 3 ng/ml Thomas NEJM Measuring Vitamin D Vitamin D and Ca absorption 1 ng/ml = 2.5 nmol/l 4ng/mL = 1 nmol/l One caveat: Most clinical assays are inaccurate CV up to 2% e.g. 24 ng/ml could be <2 or over 3 32 ng/ml Optimal Vitamin D Calcium and vitamin D supplementation in ambulatory elder population - hip fracture Desirable level begins at 3-32ng/mL (75-8 nmol/l) Do my patients need vitamin D? Evidence on fractures tells the story Hip Fractures, % Placebo Ca/D Time, months ChapuyMC et al NEJM 327:637, 1992

10 How much Vitamin D? New Guidelines recommend: 8 IU vitamin D and 1mg calcium daily for pre-menopausal women 8 IU vitamin D and 15mg Calcium daily for post-menopausal women and men over 5. Pharmacologic Treatment of PMO: Overview Treatment Hormone therapy (HT)* or ET Selective estrogen receptor modulators (SERMs): raloxifene Calcitonin Bisphosphonates* Denosumab (Prolia) rpth (Forteo) * decreasehip fractures Action Inhibit bone resorption Maintain or increase bone mass Reduce fracture risk Increases bone formation increases bone mass Slowing down the osteoclasts allow bone remodeling space to be refilled. Hundreds of bone remodeling units effected over years Usually entire skeleton remodels over 3 years AB 4/4 57 NTX Mean Value (nmol/mmol) Bone Turnover N-Telopeptide Bone Specific Alkaline Phosphatase 8 2 ALN 1 mg daily ALN 1 mg daily 7 ALN 35 mg Twice Weekly ALN 7 mg Once Weekly ALN 35 mg Twice Weekly ALN 7 mg Once Weekly Month Month Schnitzer T, et al. Aging Clin Exp Res. 2;12:1-12. Effect of Unopposed Estrogen and HRT on Spine and Hip BMD in Postmenopausal Women: The PEPI Trial Unadjusted BMD (g/cm 2 ) Spine*.92 Baseline Months Hip* Placebo CEE (.625 mg/d) CEE-MPA (cyc) CEE-MPA (con) CEE-MP (cyc) (n=125) (n=94) (n=139) (n=146) (n=136) Data shown are for compliant subjects. *P<.5vs. placebo for all comparisons. The Writing Group for the PEPI Trial. JAMA. 1996;276: Unadjusted BMD (g/cm 2 ) Baseline Months

11 % change frombaseline Effect of Raloxifene on BMD in Postmenopausal Women Without Osteoporosis Lumbar spine* Months Placebo (n=15) 3 mg raloxifene (n=152) % change frombaseline *P<.3 vs. placebo forall treatment groups at 24 months Total hip* Months 6 mg raloxifene (n=152) 15 mg raloxifene (n=147) Reprinted with permission from Delmas PD, et al. N Engl J Med. 1997;337: Cost Effectiveness of Osteoporotic Treatment NOF guidelines suggest benefit at 1 year fracture risk 2% major osteoporotic fracture or > 3% hip fracture Bisphosphonates: Women over 67 with fractures Vitamin D and calcium Elderly patients Bisphosponates approved for Postmenopausal Osteoporosis Medication Dose Interval Cost/ 3 Mon Alendronate 7mg weekly PO Weekly $17 Alendronate/cholecalciferol (Fosamax Plus D) 7 mg/2,8 IU PO weekly $354 Risedronate (Actonel) 35 mg PO weekly $925 Ibandronate (Boniva) 15 mg PO monthly $7 Ibandronate (Boniva) inj 3 mg IV over 15-3 Q 3 months $1616 per year ZoledronicAcid (Reclast) 5 mg IV in 1h Annually $5 per year* When prescribing bisphosphonates work the patient up Ensure adequate Ca and vitamin D intake Discuss: cost projected duration of Rx potential side effects: mostly GI. use TAV to follow-up NEVER cut pills IV meds may cause flu-like symptoms, rarely renal compromise may vary dose for patients with CKD stage II and III Unknown knowns unproven side effects: a fib and esophageal cancer Possible issues Osteonecrosis of the jaw (<1/1 over 5 years) Possible risk of diaphyseal fractures with long-term Rx (<<1/1 over 5 years)

12 Black, DM et al N ENGL J MED 212; 366: ? Is there magic in the dosing interval? No Several studies show prolonged effect on Bone turnover markers and maintenance of Bone Density for months to YEARS after stopping bisphosphonates Grey A. Prolonged antiresorptive activity of zoledronate: a randomized, controlled trial. J of Bone & Mineral Research. 25(1):2251, 21 Monitor calcium, vitamin D and consider drug holidays New Drugs Denosumab - humanized mouse monoclonal antibody to RANKL (a ligand that activates the osteoclasts) - blocks osteoclast differentiation, proliferation, and function. Increased BMD (McClung MR et al 26 NEJM 354:821) Change in bone density and decrease in bone turnover markers and preliminary data suggest decreased FX -subcutaneous injection twice a year Similar decrease in fracture risk over 3 years Recombinant PTH - Forteo Daily SQ injection 2 mcg for up to 2 years (limit due to osteosarcoma in rats) Very expensive but unique mode of action increases osteoblast function. May cause hypercalcemia. Contraindicated in: active malignancy renal insufficiency renal stone disease

13 Effect of Teriparatide (2µg) on Skeletal Architecture rpth Daily 2 µg SQ injection Stimulates osteoblasts Increases bone mass Decreases fracture rate Time limited $8-1, per year Follow-up Baseline Patient 1124 B3D-MC-GHAC UCSF - Jiang Is there magic in the dosing interval? No Several studies show prolonged effect on Bone turnover markers and maintenance of Bone Density for months to YEARS after stopping bisphosphonates Must be followed by antiresorptive or BMD is lost again. When/Why Should I Consider a Drug Holiday? And for How Long? Grey A. Prolonged antiresorptive activity of zoledronate: a randomized, controlled trial. J of Bone & Mineral Research. 25(1):2251, 21 Monitor calcium, vitamin D and consider drug holidays Drug Holidays: FLEX Trial Black, et al., JAMA 26. After 5 years of oral alendronate (FIT), 199 post menopausal women randomized to 5 more years of alendronate or placebo (FLEX). Drug Holidays and FLEX: BMD

14 FLEX trial Drug Holidays and FLEX: Fractures 5yrs + holiday 1 yrs Conclusions from FLEX: 5 vs. 1 yrs of alendronate Compared to 5 years, 1 years of alendronate offers: FLEX Results: Highest Risk Women For women at highest risk, defined as femoral neck T score <-2.5, five additional years of bisphosphonate did result in fewer non vertebral fractures. Stabilization of BMD Reduction in the risk of vertebral fractures No impact on the rate of non vertebral fractures Bottom Line: consider 1 yrs instead of 5 for those at highest risk of vertebral fracture: Prior hx of vertebral fracture Very low T scores or highest FRAX scores HORIZON Extension Trial HORIZON: Zoledronic acid 5mg IV or placebo annually for 3 years HORIZON Extension: Results BMD: declined slightly in the Z3P3 group vs. Z6 True for all sites (spine and hip) Z3P3 BMD still above Z baseline Vertebral fractures: lower in Z6 group HORIZON EXTENSION: Those who received ZOL randomized to more ZOL (Z6) or placebo for more three years (Z3P3) 3.% vs. 6.2% Non vertebral fractures: no difference 8.2 vs. 7.6% Hip fractures: no difference 1.3 vs. 1.4%

15 Discussing side effects and follow-up Chronic disease Fracture patients may require long-term treatment (>5 years) Preventive (prophylactic) therapy. Consider drug holiday and reassess risk Very high risk Consider combination or sequential therapy Consultation with osteoporosis expert FLEX trial follow-up Initial bone density and age predicted future fracture Bone turnover markers did not predict fracture at baseline or at 1 year post ALN. This does not help us with prevention of ONJ Bauer et al.jama Internal Medicine 214, 174(7):1126 Conclusions Risk of fracture should be high before initiating treatment with antiresorptive agents Reassessing risk and discontinuing medications is an option Communication between providers may improve patient outcomes No known protection from ONJ THANK YOU! Comments, Questions? Prevent fractures Screen patients at risk Preventive measures Treat high risk patients A fracture in a susceptible patient requires work-up and treatment Have a treatment goal and re-visit the issue annually.