1 / 51

Osteoporosis: Update 2011 Mini-Med School

Osteoporosis: Update 2011 Mini-Med School. Marc C. Hochberg, MD, MPH Professor, Departments of Medicine and Epidemiology & Public Health. Objectives. Identify common types of fractures Review current recommendations for diagnosis and treatment of postmenopausal women with osteoporosis

elke
Download Presentation

Osteoporosis: Update 2011 Mini-Med School

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Osteoporosis: Update 2011Mini-Med School Marc C. Hochberg, MD, MPH Professor, Departments of Medicine and Epidemiology & Public Health

  2. Objectives • Identify common types of fractures • Review current recommendations for diagnosis and treatment of postmenopausal women with osteoporosis • Who should be tested • Who should be treated • How should they be treated • Discuss the rare adverse events of bisphosphonate therapy

  3. Definitions of Osteoporosis • A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. • NIH Consensus Conference (2000) • Bone mineral density that is >=2.5 standard deviations below the young gender-specific mean • World Health Organization (1994)

  4. Goals for Therapy • Fracture prevention • Stabilize or increase bone mass • Provide tolerability and long-term safety • Optimize adherence

  5. Vertebral Fractures • Involve both the thoracic and lumbar spine • Only ~1/3 are associated with acute back pain • Presence of vertebral deformities is associated with chronic back pain and disability, increased risk of hospitalization and excess mortality

  6. Hip Fracture • Most serious clinical fracture • Mortality is high • 20% of patients die within 1 year • Men have higher mortality than women • Morbidity is high • 50% do not regain independence • 50% do not regain previous level of function • Patients who survive • are often not treated for osteoporosis • are at increased risk of additional fractures

  7. Rationale for Measuring BMD • Bone mineral density (BMD) • Strongly related to bone strength • Independent predictor of fracture risk • For each SD decrease in BMD, fracture risk increases 1.5 – 2.5 times • Gold standard for diagnosis of osteoporosis • Can be used to monitor efficacy of therapy

  8. How to Measure BMD • Dual Xray Absorptiometry (DXA) is the gold standard for measuring BMD • Hip (femoral neck and total hip) • Lumbar spine • Distal 1/3rd radius • Primary hyperparathyroidism • When hips and lumbar spine can’t be measured or are not valid

  9. Who Should be Tested • Women aged 65 and above • Younger postmenopausal women with clinical risk factors • Prior low trauma fracture • Current smokers • Low body weight • Family history of hip fracture • Women with medical conditions or taking medications that are associated with low bone mass or an increased rate of bone loss

  10. Endocrine diseases Hyperthyroidism Hyperparathyroidism Hypogonadism GI diseases Malabsorption syndromes Chronic liver disease Gastric operations Organ transplant Other chronic diseases Rheumatoid arthritis Chronic lung disease Malignancy Dietary disorders Vitamin D deficiency/ insufficiency Excess alcohol intake Anorexia nervosa Diseases That Can CauseSecondary Osteoporosis

  11. Medications That Can Cause Secondary Osteoporosis • Oral glucocorticoids • Excess thyroid hormone replacement • Chemotherapy • Anticonvulsants • Gonadal hormone suppression • Immunosuppressive agents

  12. Who Should Be Treated • Women with a hip or vertebral fracture • Women with BMD T-score < -2.5 at femoral neck or lumbar spine • Women with low BMD and a 10-year probability of hip fracture > 3.0% or major osteoporotic fracture > 20% based on US-adapted FRAX model

  13. US Race-Specific FRAX Model • Calculates 10-year absolute risk of major osteoporotic and hip fracture • Includes age, sex, height, weight, h/o prior fracture, family h/o hip fracture, current smoking, current alcohol consumption, current glucocorticoid use, medical conditions associated with 2ary osteoporosis, and BMD

  14. Nonpharmacologic Approaches • Calcium intake • Diet and/or supplementation with an RDA of at least 1200 mg (upper limit [UL] 2000 mg) in conjunction with vitamin D

  15. Potential Harms of Calcium Supplementation • Increased risk of renal stones when given in conjuction with vitamin D • RR = 1.17 (95% CI: 1.02, 1.34) • 5.7 events per 10,000 women-years • Increased risk of nonfatal MI • RR = 1.31 (95% CI: 1.02, 1.67) for IPD • RR = 1.27 (95% CI: 1.01, 1.59) for studies • Bolland MJ et al: BMJ 2010;341:c3691

  16. Calcium intake Diet and/or supplementation with an RDA of at least 1200 mg (upper limit [UL] 2000 mg) in conjunction with vitamin D Vitamin D supplementation Diagnose and treat deficiency or insufficiency (< 20 ng/ml) Supplement with at least 600-800 IU D3/day (UL 4000 IU/day) Nonpharmacologic Approaches

  17. Vitamin D and Fractures: Bischoff-Ferrari Meta-analysis • Systematic review of double-blind RCTs of at least 1 year duration with more than 1 fracture • 7 studies with informative data for non-vertebral fractures: RR = 0.83 (0.70, 0.98) • 5 studies with informative data for hip fractures: RR = 0.88 (0.69, 1.13) • Heterogeneity based on vitamin D dosage • Vitamin D at a dose of 700-800 IU/d, but not 400 IU/d, reduced risk of both hip and nonvertebral fractures Bischoff-Ferrari H et al: JAMA 2005;293:2257-64

  18. Vitamin D and Fractures: AHRQ-Ottawa Meta-analysis • Systematic review of double-blind RCTs of at least 1 year duration with more than 1 fracture • 13 studies with informative data for total fractures: RR = 0.90 (0.81, 1.02) • 7 studies with data for non-vertebral fractures: RR = 0.87 (0.75, 1.00) • 7 studies with informative data for hip fractures: RR = 0.83 (0.68, 1.00) • Heterogeneity based on residence of participants • Significant fracture reduction among institutionalized subjects but not among community-dwelling elders Cranney A et al: IOM 2011 report

  19. Vitamin D and the Risk of Falling FavorsVitamin D FavorsControl Odds Ratio (95% CI) Primary Analysis Pfeifer et al (2000) 0.47 (0.20–1.10) Bischoff et al (2003) 0.68 (0.30–1.54) Gallagher et al (2001) 0.53 (0.32–0.88) Dukas et al (2004) 0.69 (0.41–1.16) Graafmans et al (1996)0.91 (0.59–1.40) Pooled (uncorrected) 0.69 (0.53–0.88) Pooled (corrected) 0.78 (0.64–0.92) 0.1 0.5 1.0 5.0 10.0 Odds Ratio Bischoff-Ferrari HA. JAMA. 2004;291:1999–2006

  20. Potential Harms of Vitamin D Supplementation • Increased risk of renal stones when given in conjunction with calcium • RR = 1.17 (95% CI: 1.02, 1.34) • 5.7 events per 10,000 women-years • No clinically important adverse effects of vitamin D supplementation • Rosen CJ: NEJM 2011;364:248-54

  21. Calcium intake Diet and/or supplementation with an RDA of at least 1200 mg (upper limit [UL] 2000 mg) in conjunction with vitamin D Vitamin D supplementation Diagnose and treat deficiency or insufficiency (< 20 ng/ml) Supplement with at least 600-800 IU D3/day (UL 4000 IU/day) Regular load-bearing and muscle-strengthening exercise (no weight lifting if BMD in spine is low) Fall prevention advice Smoking cessation Avoid excess alcohol intake Home safety evaluation Nonpharmacologic Approaches

  22. Current FDA-Approved Treatments for Postmenopausal Osteoporosis: 2011 • Bisphosphonates • Alendronate • Risedronate • Ibandronate • Zoledronic acid • Calcitonin • Denosumab • Hormone therapy • Raloxifene • Teriparatide

  23. Pharmacologic Approaches: Summary • All FDA-approved treatments reduce the incidence of vertebral fractures • Some, but not all, reduce the incidence of non-vertebral fractures • Some, but not all, of the drugs that reduce the incidence of non-vertebral fractures also reduce the incidence of hip fractures

  24. WHI Clinical Trials of HT • Two large, parallel group, randomized, placebo-controlled trials sponsored by NIH • Unopposed CEE vs placebo (E-alone study) • CEE plus MPA vs placebo (E+P study) • Objective: To evaluate the balance of chronic disease risks and benefits of postmenopausal HT • Primary outcomes • CHD (nonfatal MI, CHD death) • Invasive breast cancer • Approximately 8 years of follow up were planned for each trial HT = hormone therapy; CEE = conjugated equine estrogens; MPA = medroxyprogesterone acetate. The Women's Health Initiative Study Group. Control Clin Trials. 1998;19:61-109.

  25. What Happened to the WHI Clinical Trials of HT? • E+P trial stopped by the Data Safety Monitoring Board in July 2002 after a mean follow-up of 5.2 years1 • Breast cancer risk crossed pre-specified monitoring boundary • Global index indicated trend towards greater risk than benefit • E-alone trial stopped by NIH in March 2004 after a mean follow-up of 6.8 years2 • Trend toward increased risk of stroke without overall benefit 1Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33; 2Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.

  26. WHI Fracture Results • E+P used an average of 5.6 years1 • ↓ hip fractures 33% • ↓ clinical vertebral fractures 35% • ↓ forearm/wrist fractures 29% • ↓ total fractures 24% • Unopposed E used an average of 6.8 years2 • ↓ hip fractures 39% • ↓ clinical vertebral fractures 38% • ↓ total fractures 30% 1Cauley JA, et al. JAMA. 2003;290:1729-38. 2Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-12.

  27. WHI Fracture Results:Clinical Implications • Women treated with E alone or E+P for menopausal symptoms do not need another anti-resorptive agent to reduce either the decline in BMD or risk of fracture • HT is the only therapy that has been demonstrated to prevent fractures in a population of postmenopausal women at relatively low risk of fracture

  28. Selective Estrogen Receptor Modulators (SERMs) • Approved for prevention and treatment of post-menopausal osteoporosis • Reduces risk of ER+ breast cancer • Can be used with other nonhormonal therapies • Adverse effects include hot flashes, risk of VTE • Raloxifene, others in clinical trials • Binds to ERs • Effects on many tissues • Bone effects mainly anti-catabolic  • increases BMD • reduces risk of vertebral fractures • Does not reduce risk of nonvertebral fractures

  29. Bisphosphonates • Drug class of choice for treatment • Oral: alendronate or risedronate • IV: zoledronic acid • Contraindications • Impaired swallowing (oral only) • eGFR < 35 ml/min • Hypocalcemia • Vitamin D deficiency Favus MJ: NEJM 2010;363:2027-35.

  30. Evidence-Based Review ALN Trials:Non-vertebral Fractures • Data on incidence of NVFx in 9 trials • Only 5 trials could be pooled for effects of 10 mg daily dose • Pooled estimate for RR = 0.84 (0.74–0.94) for all non-vertebral fractures at doses of 10 mg or higher • RR reduction greater in the 4 treatment trials (RR=0.77 [0.64, 0.92]) • No difference using T-score of <-2.5 or <-2.0 as cut-point • Pooled estimate for hip fracture derived from 6 trials • RR = 0.61 (95% CI 0.40, 0.92) Wells G et al: Cochrane Database Syst Rev 2008;(1):CD001155.

  31. Evidence-Based Review of RIS Trials: Nonvertebral Fractures • Pooled estimate from 4 treatment trials for all nonvertebral fractures of RR=0.80 (0.72–0.90) • Results consistent across trials • Pooled estimate from 3 treatment trials for hip fractures • RR = 0.74 (95% CI: 0.59, 0.94) Wells G et al: Cochrane Database Syst Rev 2008;(1)CD004523.

  32. Effect of Ibandronate on Fracture Risk in Women with PMO • Post-hoc individual patient data meta-analysis of data from 4 phase III RCTs of at least 2 years duration • Subjects categorized by estimated annual cumulative exposure: low, medium, high • Patients in the high ACE group (either 150 mg orally once monthly, 2 mg IV bimonthly or 3 mg IV quarterly) had a lower adjusted incidence of non-vertebral fractures than women in pooled placebo groups • RR = 0.70 (0.50. 0.99) for all non-vertebral fractures • RR = 0.66 (0.45, 0.96) for “Big 6” fracture sites Harris S, et al: Curr Med Res Opin 2008:24;237-45.

  33. Once- Yearly Zoledronic Acid: The Horizon Trial • 7765 postmenopausal women aged 65 to 89 years randomized to IV zoledronic acid 5 mg or PBO annually for 3 years • Inclusion criteria • Femoral neck BMD T score < -2.5 • T-score < -1.5 and morphometric VFx (2 mild or 1 mod) • Stratified randomization • 1: No concomitant OP medication at baseline • 2: OP meds, other than BPs, at baseline Black DM et al: NEJM 2007;356:1809-22

  34. Once-Yearly Zoledronic Acid: The Horizon Trial Relative risk Spine 0.30 (0.24,0.38) Hip 0.59 (0.42,0.83) Nonvert 0.75 (0.64,0.87) Clinical 0.67 (0.58,0.77) Black DM et al: NEJM 2007;356:1809-22

  35. Comparative Efficacy of N-containing Bisphosphontes Hochberg M: Curr Osteoporos Rep 2008;6:89-94.

  36. Comparative Efficacy of N-containing Bisphophonates • Mixed treatment comparison (MTC) of reduction in vertebral fractures • 7 placebo-controlled trials • ZA more likely to be associated with greater risk reduction than oral BPs • ZA vs ALN OR = 0.54 (0.39, 0.75) • ZA vs RIS OR = 0.49 (0.34, 0.69) • ZA vs IBAN OR = 0.57 (0.36, 0.92) Jansen JP et al: CMRO 2009;25:1861-8 and Semin Arthritis Rheum 2011;40:275-84.

  37. Comparative Efficacy of N-containing Bisphosphontes Jansen JP et al: Semin Arthritis Rheum 2011;40:275-84.

  38. Bisphosphonates Adverse Events • Upper GI complaints • Acute phase reaction (IV >>> oral) • Erosive esophagitis • Esophageal cancer • Osteonecrosis of the jaw • Atypical femoral fractures Favus MJ: NEJM 2010;363:2027-35.

  39. Potential Harms of BPs: Esophageal Cancer Two studies that analyzed data from the GPRD Study 1 (cohort study) found no increase in risk (HR = 1.07 [95% CI: 0.77, 1.49]) with mean follow-up of 4.5 years • Cardwell CR et al: JAMA 2010;304:657-63. Study 2 (case-control) found an increase in risk (OR = 1.30 [95% CI: 1.02, 1.66]) with mean follow-up of 7.5 years. Significant dose and duration response relationships with excess risk for >10 Rxs and duration of use >3 years • Green J et al: BMJ 2010;341:c4444.

  40. Potential Harms of BPs: Subtrochanteric Fractures Several studies have examined this relationship Most recent, a nested case-control study of older women who received Rx for oral bisphosphonate: 716 subtrochanteric and 9723 hip fractures • Park-Wyllie LY et al: JAMA 2011;305:783-9. aOR = 2.74 (95% CI: 1.25, 6.02) for long-term use (>5 years) based on 121 cases Significant reduction in risk of hip fractures for both intermediate (3-5 years) and long-term use • Intermediate aOR = 0.86 (0.73, 1.00) • Long-term aOR = 0.76 (0.63, 0.93)

  41. Anabolic Therapy: Teriparatide • Recombinant human PTH 1-34 • PTH 1-84 and other analogs currently under investigation • Indicated for treatment • of women with PMO at high risk for fracture • to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture • Not for use in patients with Paget’s disease, hypercalcemia, renal disease or skeletal cancer

  42. Effect of Teriparatide on Risk of New Vertebral Fractures RR 0.31 (95% CI, 0.19 to 0.50)* RR 0.35 (95% CI, 0.22 to 0.55)* 14 0% 12 25% 10 % of Women 8 Risk Reduction (RR) 50% 6 4 75% 2 19 64 22 100% 0 Placebo (n=448) rhPTH 20 (n=444) rhPTH 40 (n=434) Number of women who had ≥1 fracture *P<0.001 vs placebo.

  43. Effect of Teriparatide on Risk of Non-vertebral Fractures RR 0.46 (95% CI, 0.25 to 0.86)* RR 0.47 (95% CI, 0.25 to 0.88)† 30 14 14 (n=544) (n=541) (n=552) Number of women who had ≥1 nonvertebral fracture *P=0.01 vs placebo. †P=0.02 vs placebo.

  44. Adverse Events With Teriparatide Placebo 8 (2) 1 (0) 41 (7) 45 (8) 6 (1) 32 (6) PTH 20 60 (11)‡ 16 (3 )‡ 51 (9) 44 (8) 17 (3)* 35 (6) PTH 40 153 (28)‡ 53 (10)‡ 98 (18)‡ 72 (13)† 13 (2) 59 (11)§ ≥1 elevated sCa Confirmed high sCa Nausea Headache Leg cramps Withdrawn for AE No. of Adverse Events (% of total) Reported *P=0.02 vs placebo. †P = 0.01 vs placebo. ‡P< 0.001 vs placebo. §P=0.004 vs placebo.

  45. Denosumab: The Freedom Trial • 7868 postmenopausal women aged 60 to 90 years randomized to denosumab 60 mg subq or PBO q6months for 3 years • Inclusion criteria • Femoral neck BMD T score < -2.5 • Primary endpoints • New vertebral fractures • Secondary endpoints • Time to 1st non-vertebral fracture • Time to 1st hip fracture • Change in bone mineral density • Change in bone turnover markers Cummings SR et al: NEJM 2009;361:756-65.

  46. Denosumab: The Freedom Trial Relative risk Spine 0.32 (0.26,0.41) Hip 0.60 (0.37,0.97) Nonvert 0.80 (0.67,0.95) Cummings SR et al: NEJM 2009;361:756-65.

  47. Several drugs reduce the risk of vertebral fractures Calcitonin Raloxifene Hormone Rx Alendronate Risedronate Ibandronate Zoledronic acid Teriparatide Denosumab Some drugs reduce the risk of non-spine fractures Hormone Rx* Alendronate* Risedronate* Ibandonate (?) Zoldedronic acid* Teriparatide Denosumab* Evidence-Based Review of Osteoporosis Trials *Also reduce the risk of hip fracture

  48. Safety and Tolerability Issues • Bisphosphonates • GI tolerability, ONJ, Atypical femur fractures • Hormone therapy • CV thrombotic events, Breast Ca, others • Raloxifene • Venous thrombotic events • Teriparatide • Hypercalcemia • Denosumab • Increased risk of infections

  49. Treatments Under Development • SERMs • Bazedoxifene, lasofoxifene • Oral calcitonin • Transdermal PTH • Cathepsin K inhibitors • Sclerostin monoclonal antibody • rhIGF-1 Kawai M et al: Nat Rev Drug Discov 2011;10:141-56

  50. Recommendations: 2011 • For postmenopausal women with osteoporosis • Oral bisphosphonate (alendronate or risedronate) • Zoledronic acid (if contraindication to or intolerant of oral BP) • Teriparatide (“severe OP” or contraindication to, failure of or unable to tolerate BPs) • Denosumab (as above plus contraindication to or unable to tolerate TPTH) All pharmacologic agents should be added to a background of calcium and vitamin D supplementation and education in non-pharmacologic treatment strategies.

More Related