Osteoporosis: Pathophysiology and Management Dr. Frank Waldron-Lynch M.D Ph D MRCPI MRCP(UK), Section of Endocrinology, Ya...
Outline <ul><li>Definition of osteoporosis </li></ul><ul><li>Pathogenesis </li></ul><ul><li>Diagnosis </li></ul><ul><li>Th...
Classic presentation
Definition <ul><li>Clinical </li></ul><ul><ul><li>Loss of bone mass sufficient to significantly increase the risk of fract...
Epidemiology   <ul><li>United States </li></ul><ul><ul><li>10 million individuals with osteoporosis </li></ul></ul><ul><ul...
Pathogenesis <ul><li>Peak bone mass </li></ul><ul><li>Etiology Bone loss </li></ul><ul><li>Age </li></ul><ul><li>Secondary...
Peak Bone Mass <ul><li>Genetically determined </li></ul><ul><ul><li>70-75% </li></ul></ul><ul><ul><li>Driven by sex hormon...
Factors Affecting Peak Bone Mass  <ul><li>Delay or Failure of puberty </li></ul><ul><ul><li>Primary Hypogonadism  </li></u...
Etiology of Bone loss in Osteoporosis Primary cause is estrogen deficiency + OSTEOCLAST - RESORPTION OSTEOBLAST - FORMATION
Estrogen Deficiency <ul><li>Women  </li></ul><ul><ul><li>Occurs earlier </li></ul></ul><ul><ul><li>At menopause bone loss ...
Riggs B. N Engl J Med 1986;314:1676   Age (years) Annual Fracture Incidence, per 100,000 0 1000 2000 3000 4000 35  45 55 6...
Hip Fracture Risk for a Given T-score Depends on Age 10 year risk of fracture in Swedish women
Secondary causes of accelerated  bone loss <ul><li>Inherited disorders </li></ul><ul><ul><li>Osteogenesis imperfecta tarda...
Secondary causes of accelerated  bone loss <ul><li>Respiratory </li></ul><ul><ul><li>Cystic fibrosis </li></ul></ul><ul><l...
Secondary causes of accelerated  bone loss <ul><li>Endocrine </li></ul><ul><ul><li>Hyperthyroidism </li></ul></ul><ul><ul>...
Secondary causes of accelerated  bone loss <ul><li>Drugs </li></ul><ul><ul><li>Glucocorticoids </li></ul></ul><ul><ul><li>...
Diagnosis <ul><li>Approach to patient </li></ul><ul><li>Investigations </li></ul><ul><ul><li>Bloods </li></ul></ul><ul><ul...
Approach to patient with suspected  osteoporosis – guide investigations <ul><li>Focused history </li></ul><ul><ul><li>Frac...
Focused history <ul><li>Medications </li></ul><ul><ul><li>Any drugs effect BMD </li></ul></ul><ul><ul><li>Any drug affect ...
Examination – Key points <ul><li>Weight </li></ul><ul><ul><li>Calculate body mass index </li></ul></ul><ul><li>Height </li...
Investigations <ul><li>Bloods -Basic </li></ul><ul><ul><li>CBC </li></ul></ul><ul><ul><li>Electrolytes and eGFR </li></ul>...
Bone re modelling – Bone markers OSTEOCLAST - RESORPTION OSTEOBLAST - FORMATION  Intact Osteocalcin (OC I )    Mineralizat...
Bone markers - Use <ul><li>Diagnosis </li></ul><ul><ul><li>Identification high bone turnover states </li></ul></ul><ul><ul...
Direct measurement of BMD by DXA and  as well as CT allows us  to diagnose osteopenia
<ul><li>Bone mineral density testing  </li></ul><ul><ul><li>Important means of assessing fracture risk </li></ul></ul><ul>...
FRAX -  Fracture Risk Assessment Tool <ul><li>WHO has recently released FRAX, the WHO Fracture Risk Assessment Tool.  Pati...
FRAX - Use
FRAX variables
Treatment recommended <ul><li>Consider FDA-approved medical therapies in   postmenopausal women and men aged 50 years and ...
Caveats regarding FRAX <ul><li>Prospective data on the efficacy of FRAX in making pharmacologic treatment decisions are la...
Non Pharmacologic Treatment <ul><li>Essential  </li></ul><ul><ul><li>Are as important as any medication </li></ul></ul><ul...
Calcium and Vitamin D <ul><li>Calcium </li></ul><ul><ul><li>Total sufficient to prevent calcium malabsorption  and seconda...
Effects of Vitamin D supplementation <ul><li>Double-blind community-based RCT in the UK </li></ul><ul><li>2686 individuals...
Drug Therapy for Low Bone Mass Prior to drug therapy treat any secondary causes
Drug Therapy for Low Bone Mass <ul><li>Bisphosphates </li></ul><ul><li>Parathyroid hormone </li></ul><ul><li>Selective Est...
Targeting the bone resorption side of the bone remodeling cycle
Bisphosphonates ETIDRONATE ETIDRONATE PAMIDRONATE ALENDRONATE IBANDRONATE RISEDRONATE TILUDRONATE CLODRONATE CLODRONATE ZO...
Bisphosphonates are the most effective  antiresorptive agents available for the  prevention and treatment of  bone loss.
Anti-fracture efficacy of bisphosphonates in  osteoporotic women Vertebral fracture Hip  fracture Non-vertebral  fracture ...
When can the patient have a drug holiday from bisphosphonates?
The Flex Trial <ul><li>Time to non vertebral fracture </li></ul><ul><li>Time to vertebral fracture after 5 years  </li></u...
 
Management of patients taking bisphosphates <ul><li>Dental examination prior to treatment </li></ul><ul><li>Repeat BMD 1-2...
Raloxifene  <ul><li>Selective Estrogen Receptor Modulators (SERMs)  </li></ul><ul><li>Raloxifene </li></ul><ul><ul><li>Red...
Denosumab: therapy targeted at the RANKL/OPG system Not approved by FDA yet
Mechanism of action Denosumab Osteoclast precursor Osteoblast   Denosumab Humanized anti-RANK-Ligand RANK OPG RANK -Ligand
<ul><li>7,868 women ages 60 to 90 </li></ul><ul><li>Mean L-spine T-score -2.8 </li></ul><ul><li>23% of had prevalent verte...
Targeting the  bone formation  side of the bone remodeling cycle
Parathyroid Hormone
PTH - Mechanism of Action PTH binds to cell surface G protein-coupled receptor Decreased apoptosis and stimulation of oste...
Effect of rhPTH(1-34) on the Risk of New Vertebral Fractures * p <0.001 vs. Placebo Risk Reduction (RR)   Placebo (n=448) ...
PTH plus ALENDRONTE may not be  better than PTH alone
PTH <ul><li>Advantages </li></ul><ul><ul><li>First anabolic therapy </li></ul></ul><ul><ul><li>Good efficacy data </li></u...
PTH <ul><li>Disadvantages </li></ul><ul><ul><li>Must be given by subcutaneous injection </li></ul></ul><ul><ul><li>Risk Os...
Summary <ul><li>Osteoporosis is an important public health problem </li></ul><ul><li>Accurate diagnosis and treatment requ...
Summary <ul><li>A variety or antiresorptive agents are available for the prevention and treatment of osteoporosis of which...
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Osteoporosis: Pathophysiology and Management Dr. Frank ...

  1. 1. Osteoporosis: Pathophysiology and Management Dr. Frank Waldron-Lynch M.D Ph D MRCPI MRCP(UK), Section of Endocrinology, Yale University School of Medicine.
  2. 2. Outline <ul><li>Definition of osteoporosis </li></ul><ul><li>Pathogenesis </li></ul><ul><li>Diagnosis </li></ul><ul><li>Therapy </li></ul><ul><li>Future development </li></ul>http://www.med.yale.edu/intmed/endocrin/patient/bonecenter.html
  3. 3. Classic presentation
  4. 4. Definition <ul><li>Clinical </li></ul><ul><ul><li>Loss of bone mass sufficient to significantly increase the risk of fracture </li></ul></ul><ul><li>Diagnostic </li></ul><ul><ul><li>T score – number of standard deviations above or below the mean for a similar healthy 30 year old </li></ul></ul><ul><ul><ul><li>Normal BMD = T: 0 to -1 </li></ul></ul></ul><ul><ul><ul><li>Osteopenia BMD = T: -1 to -2.5 </li></ul></ul></ul><ul><ul><ul><li>Osteoporosis BMD = T: less than -2.5 </li></ul></ul></ul><ul><ul><li>Z score – number of standard deviations above or below the mean for the patients age, sex and ethnicity </li></ul></ul>
  5. 5. Epidemiology <ul><li>United States </li></ul><ul><ul><li>10 million individuals with osteoporosis </li></ul></ul><ul><ul><li>34 million individuals with osteopenia </li></ul></ul><ul><li>Fracture Risks over age 50 </li></ul><ul><ul><li>50% of women will have an osteoporosis related fracture </li></ul></ul><ul><ul><li>25 % of men will have an osteoporosis related fracture </li></ul></ul><ul><li>Estimated costs </li></ul><ul><ul><li>Direct health care $14 billion each year </li></ul></ul>http://www.niams.nih.gov/Health_Info/Bone/Osteoporosis/default.asp
  6. 6. Pathogenesis <ul><li>Peak bone mass </li></ul><ul><li>Etiology Bone loss </li></ul><ul><li>Age </li></ul><ul><li>Secondary causes </li></ul>
  7. 7. Peak Bone Mass <ul><li>Genetically determined </li></ul><ul><ul><li>70-75% </li></ul></ul><ul><ul><li>Driven by sex hormones during puberty </li></ul></ul><ul><ul><li>Depends on site measured – spine, femur, radius </li></ul></ul><ul><li>Ethnicity </li></ul><ul><ul><li>Chinese American later than Caucasians </li></ul></ul><ul><li>Women </li></ul><ul><ul><li>Peak accrual ages 11-15 </li></ul></ul><ul><ul><li>95 per cent achieved by late teens </li></ul></ul><ul><li>Men </li></ul><ul><ul><li>Peak accrual later teens </li></ul></ul><ul><ul><li>Maximum spine age 20 </li></ul></ul><ul><ul><li>Radius and femur by mid twenties </li></ul></ul>
  8. 8. Factors Affecting Peak Bone Mass <ul><li>Delay or Failure of puberty </li></ul><ul><ul><li>Primary Hypogonadism </li></ul></ul><ul><ul><ul><li>Turners syndrome </li></ul></ul></ul><ul><ul><ul><li>Klinefelter syndrome </li></ul></ul></ul><ul><ul><ul><li>Absent cervix, uterus, cervix and/or vagina </li></ul></ul></ul><ul><ul><ul><li>Cryptorchidism </li></ul></ul></ul><ul><ul><ul><li>Chemotherapy, Radiotherapy </li></ul></ul></ul><ul><ul><ul><li>Chronic systemic diseases </li></ul></ul></ul><ul><ul><li>Secondary Hypogonadism </li></ul></ul><ul><ul><ul><li>Kallmann syndrome </li></ul></ul></ul><ul><ul><ul><li>CNS tumors, infiltrative disorders </li></ul></ul></ul><ul><ul><ul><li>Malnutrition </li></ul></ul></ul><ul><ul><ul><li>Chronic systemic illness </li></ul></ul></ul>
  9. 9. Etiology of Bone loss in Osteoporosis Primary cause is estrogen deficiency + OSTEOCLAST - RESORPTION OSTEOBLAST - FORMATION
  10. 10. Estrogen Deficiency <ul><li>Women </li></ul><ul><ul><li>Occurs earlier </li></ul></ul><ul><ul><li>At menopause bone loss rates to increase by 2 to 6 fold </li></ul></ul><ul><ul><li>For subsequent 6-8 years </li></ul></ul><ul><ul><li>Impairs calcium absorption from gut </li></ul></ul><ul><li>Men </li></ul><ul><ul><li>Testosterone declines age </li></ul></ul><ul><ul><li>Estrogen declines age </li></ul></ul><ul><ul><li>Both androgens and estrogen contribute </li></ul></ul>
  11. 11. Riggs B. N Engl J Med 1986;314:1676 Age (years) Annual Fracture Incidence, per 100,000 0 1000 2000 3000 4000 35 45 55 65 75 85+ Vertebrae Hip Colles' Fracture Risk with Aging Caucasian women
  12. 12. Hip Fracture Risk for a Given T-score Depends on Age 10 year risk of fracture in Swedish women
  13. 13. Secondary causes of accelerated bone loss <ul><li>Inherited disorders </li></ul><ul><ul><li>Osteogenesis imperfecta tarda </li></ul></ul><ul><ul><li>Thallasemia </li></ul></ul><ul><li>Amenorrhea </li></ul><ul><ul><li>Eating disorders </li></ul></ul><ul><ul><li>Low weight </li></ul></ul><ul><ul><li>Excess Exercise </li></ul></ul><ul><ul><li>Female athlete triad </li></ul></ul><ul><ul><ul><li>Energy deficiency </li></ul></ul></ul><ul><ul><ul><li>Low bone mineral density </li></ul></ul></ul><ul><ul><ul><li>Amenorrhea </li></ul></ul></ul><ul><ul><li>Premature ovarian failure </li></ul></ul>
  14. 14. Secondary causes of accelerated bone loss <ul><li>Respiratory </li></ul><ul><ul><li>Cystic fibrosis </li></ul></ul><ul><li>Gastrointestinal </li></ul><ul><ul><li>Celiac sprue </li></ul></ul><ul><ul><li>Post Gastric by pass </li></ul></ul><ul><ul><li>Inflammatory bowel disease </li></ul></ul><ul><li>Renal </li></ul><ul><ul><li>Idiopathic hypercalciuria </li></ul></ul><ul><ul><li>Chronic renal failure </li></ul></ul><ul><li>Post organ transplant </li></ul><ul><ul><li>Immunosuppressive therapy </li></ul></ul>
  15. 15. Secondary causes of accelerated bone loss <ul><li>Endocrine </li></ul><ul><ul><li>Hyperthyroidism </li></ul></ul><ul><ul><li>Hyperparathyroidism </li></ul></ul><ul><ul><li>Cushing’s syndrome </li></ul></ul><ul><ul><li>Hypogonadism </li></ul></ul><ul><ul><li>Vitamin D deficiency </li></ul></ul><ul><li>Rheumatology </li></ul><ul><ul><li>Rheumatoid arthritis </li></ul></ul><ul><ul><li>Seronegative athropathies </li></ul></ul><ul><li>Lifestyle </li></ul><ul><ul><li>Smoking </li></ul></ul><ul><ul><li>Alcohol </li></ul></ul>
  16. 16. Secondary causes of accelerated bone loss <ul><li>Drugs </li></ul><ul><ul><li>Glucocorticoids </li></ul></ul><ul><ul><li>Cyclosporine </li></ul></ul><ul><ul><li>Anti seizure medications </li></ul></ul><ul><ul><ul><li>Phenobarbital </li></ul></ul></ul><ul><ul><ul><li>Phenytoin </li></ul></ul></ul><ul><ul><li>Heparin </li></ul></ul><ul><ul><li>Chemotherapy </li></ul></ul><ul><ul><ul><li>Aromatase inhibitors </li></ul></ul></ul><ul><ul><li>Thyroxine </li></ul></ul><ul><ul><ul><li>Over replacement </li></ul></ul></ul>
  17. 17. Diagnosis <ul><li>Approach to patient </li></ul><ul><li>Investigations </li></ul><ul><ul><li>Bloods </li></ul></ul><ul><ul><li>Urine </li></ul></ul><ul><ul><li>Imaging </li></ul></ul><ul><li>FRAX use </li></ul><ul><li>Calcium and Vitamin D </li></ul>
  18. 18. Approach to patient with suspected osteoporosis – guide investigations <ul><li>Focused history </li></ul><ul><ul><li>Fracture history </li></ul></ul><ul><ul><li>Loss of height </li></ul></ul><ul><ul><li>Exercise </li></ul></ul><ul><ul><li>Menstrual history </li></ul></ul><ul><ul><li>Hypogonadism men </li></ul></ul><ul><ul><li>Diet </li></ul></ul><ul><ul><li>Smoking </li></ul></ul><ul><ul><li>Alcohol </li></ul></ul><ul><li>Past medical history </li></ul><ul><ul><li>Secondary causes </li></ul></ul>
  19. 19. Focused history <ul><li>Medications </li></ul><ul><ul><li>Any drugs effect BMD </li></ul></ul><ul><ul><li>Any drug affect calcium absorption </li></ul></ul><ul><li>Family history </li></ul><ul><ul><li>History osteoporosis </li></ul></ul><ul><li>Systems review </li></ul><ul><ul><li>Gastrointestinal system </li></ul></ul><ul><ul><ul><li>GERD </li></ul></ul></ul><ul><ul><ul><li>Esophageal stricture </li></ul></ul></ul><ul><ul><ul><li>Malabsorption </li></ul></ul></ul>
  20. 20. Examination – Key points <ul><li>Weight </li></ul><ul><ul><li>Calculate body mass index </li></ul></ul><ul><li>Height </li></ul><ul><ul><li>Measure and follow </li></ul></ul><ul><ul><li>Loss greater than 1 inch may indicate spinal fracture </li></ul></ul><ul><li>Muscular skeletal </li></ul><ul><ul><li>Spine </li></ul></ul><ul><ul><ul><li>Deformity </li></ul></ul></ul><ul><ul><ul><li>Tenderness </li></ul></ul></ul><ul><ul><ul><li>Mobility </li></ul></ul></ul><ul><ul><li>Muscle strength </li></ul></ul><ul><ul><ul><li>Proximal muscle weakness </li></ul></ul></ul>
  21. 21. Investigations <ul><li>Bloods -Basic </li></ul><ul><ul><li>CBC </li></ul></ul><ul><ul><li>Electrolytes and eGFR </li></ul></ul><ul><ul><li>Serum calcium and phosphate </li></ul></ul><ul><ul><li>TSH </li></ul></ul><ul><ul><li>Testosterone (Men) </li></ul></ul><ul><ul><li>Serum protein electrophoresis </li></ul></ul><ul><ul><li>Bone markers (consider) </li></ul></ul><ul><li>Urine </li></ul><ul><ul><li>24 hour urine </li></ul></ul><ul><ul><li>Volume </li></ul></ul><ul><ul><li>Creatinine and calcium </li></ul></ul>
  22. 22. Bone re modelling – Bone markers OSTEOCLAST - RESORPTION OSTEOBLAST - FORMATION Intact Osteocalcin (OC I ) Mineralization Bone Alkaline phosphatase (Bone AP) Maturation Deoxypyridinoline (fDPD /Cr ) N-Terminal cross-linking telopeptide (NTx/Cr) Procollagen Type 1N Propeptide (PINP) Synthesis
  23. 23. Bone markers - Use <ul><li>Diagnosis </li></ul><ul><ul><li>Identification high bone turnover states </li></ul></ul><ul><ul><li>Not as well validated as DXA </li></ul></ul><ul><li>Monitor therapy </li></ul><ul><ul><li>Commencing </li></ul></ul><ul><ul><li>During treatment </li></ul></ul><ul><ul><li>Urinary Ntx </li></ul></ul><ul><ul><ul><li>Should decrease on bisphosphates </li></ul></ul></ul>
  24. 24. Direct measurement of BMD by DXA and as well as CT allows us to diagnose osteopenia
  25. 25. <ul><li>Bone mineral density testing </li></ul><ul><ul><li>Important means of assessing fracture risk </li></ul></ul><ul><ul><li>Not stand alone test </li></ul></ul><ul><li>Other risk factors have impact on fracture risk </li></ul><ul><ul><li>occasionally more significant impact than bone density results alone </li></ul></ul><ul><ul><li>Glucorticoids </li></ul></ul><ul><li>All known risk factors should be considered when deciding to treat patients </li></ul><ul><ul><li>Mostly treating patients based on risk </li></ul></ul><ul><ul><li>No overt disease </li></ul></ul><ul><li>We need better tools for assessing fracture risk </li></ul>Bone mineral density testing
  26. 26. FRAX - Fracture Risk Assessment Tool <ul><li>WHO has recently released FRAX, the WHO Fracture Risk Assessment Tool. Patients and clinicians can access this tool at: </li></ul><ul><li>http://www.shef.ac.uk/FRAX </li></ul><ul><ul><li>Data from 9 cohorts around the world </li></ul></ul><ul><ul><li>Validated in 11 independent cohorts with similar geographic distribution </li></ul></ul>
  27. 27. FRAX - Use
  28. 28. FRAX variables
  29. 29. Treatment recommended <ul><li>Consider FDA-approved medical therapies in postmenopausal women and men aged 50 years and older, based on the following: </li></ul><ul><ul><li>A hip or vertebral fracture </li></ul></ul><ul><ul><li>T-score ≤ -2.5 at the femoral neck or spine after appropriate evaluation to exclude secondary causes </li></ul></ul><ul><ul><li>Low bone mass (T-score between -1.0 and -2.5 at the femoral neck or spine) and a 10-year probability of a hip fracture ≥ 3% or a 10-year probability of a major osteoporosis-related fracture ≥ 20% </li></ul></ul><ul><ul><li>Clinicians judgment and/or patient preferences may indicate treatment for people with 10-year fracture probabilities above or below these levels </li></ul></ul>
  30. 30. Caveats regarding FRAX <ul><li>Prospective data on the efficacy of FRAX in making pharmacologic treatment decisions are lacking </li></ul><ul><ul><li>Can osteoporosis medication help equally well with all risk factors? (likely not!) </li></ul></ul><ul><ul><li>That is, not everyone with a high FRAX should be treated with a medication </li></ul></ul><ul><ul><li>We need intervention trials with FRAX as an outcome </li></ul></ul><ul><li>It does not capture spinal osteoporosis </li></ul>
  31. 31. Non Pharmacologic Treatment <ul><li>Essential </li></ul><ul><ul><li>Are as important as any medication </li></ul></ul><ul><li>Nutritional </li></ul><ul><ul><li>Calcium </li></ul></ul><ul><ul><li>Vitamin D </li></ul></ul><ul><ul><li>Vitamin A </li></ul></ul><ul><li>Lifestyle </li></ul><ul><ul><li>Smoking </li></ul></ul><ul><ul><li>Exercise </li></ul></ul><ul><li>Falls risk reduction </li></ul>
  32. 32. Calcium and Vitamin D <ul><li>Calcium </li></ul><ul><ul><li>Total sufficient to prevent calcium malabsorption and secondary hyperprathyroidism </li></ul></ul><ul><ul><li>Test adequate by 24 hour urine if eGFR > 60cc/min </li></ul></ul><ul><ul><li>Total daily intake 1500 mg/day </li></ul></ul><ul><li>Vitamin D </li></ul><ul><ul><li>Aim serum 25(OH) vitamin D > 25 ng/dl (ideally 25-35) </li></ul></ul><ul><ul><li>Total daily intake 800 IU </li></ul></ul><ul><ul><li>Higher if malabsorption </li></ul></ul>
  33. 33. Effects of Vitamin D supplementation <ul><li>Double-blind community-based RCT in the UK </li></ul><ul><li>2686 individuals (2037 men; 649 women) </li></ul><ul><ul><li>Over age 65 </li></ul></ul><ul><li>100,000 U of vitamin D3 orally every 4 months for 5 years </li></ul><ul><li>mailed to the study subjects so compliance not confirmed </li></ul>Trivedi et al. BMJ;326:469
  34. 34. Drug Therapy for Low Bone Mass Prior to drug therapy treat any secondary causes
  35. 35. Drug Therapy for Low Bone Mass <ul><li>Bisphosphates </li></ul><ul><li>Parathyroid hormone </li></ul><ul><li>Selective Estrogen Receptor Modulators </li></ul><ul><li>Denosumab </li></ul>
  36. 36. Targeting the bone resorption side of the bone remodeling cycle
  37. 37. Bisphosphonates ETIDRONATE ETIDRONATE PAMIDRONATE ALENDRONATE IBANDRONATE RISEDRONATE TILUDRONATE CLODRONATE CLODRONATE ZOLEDRONATE
  38. 38. Bisphosphonates are the most effective antiresorptive agents available for the prevention and treatment of bone loss.
  39. 39. Anti-fracture efficacy of bisphosphonates in osteoporotic women Vertebral fracture Hip fracture Non-vertebral fracture Alendronate (Fosamax®) √ √ √ Risedronate (Actonel®) √ √ √ Zolendronate (Reclast®) √ √ √ Ibandronate (Boniva® √ ? √
  40. 40. When can the patient have a drug holiday from bisphosphonates?
  41. 41. The Flex Trial <ul><li>Time to non vertebral fracture </li></ul><ul><li>Time to vertebral fracture after 5 years </li></ul>JAMA 296:2927
  42. 43. Management of patients taking bisphosphates <ul><li>Dental examination prior to treatment </li></ul><ul><li>Repeat BMD 1-2 years of treatment </li></ul><ul><ul><li>Demonstrate efficacy </li></ul></ul><ul><li>Check BMD 1-2 years later </li></ul><ul><ul><li>Improve patient compliance </li></ul></ul><ul><li>5 years </li></ul><ul><ul><li>Stop drug individuals with a good response </li></ul></ul><ul><ul><li>No longer osteoporotic </li></ul></ul><ul><li>10 years </li></ul><ul><ul><li>Stable BMD </li></ul></ul><ul><ul><li>No recent fractures </li></ul></ul>
  43. 44. Raloxifene <ul><li>Selective Estrogen Receptor Modulators (SERMs) </li></ul><ul><li>Raloxifene </li></ul><ul><ul><li>Reduces vertebral fracture </li></ul></ul><ul><ul><li>No reduction in hip fracture </li></ul></ul><ul><li>Reserve use with women without hip involvement </li></ul><ul><li>Other beneficial actions </li></ul><ul><ul><li>Reduces risk invasive breast cancer </li></ul></ul><ul><ul><li>No increase on cardiovascular motality of mobidity </li></ul></ul>
  44. 45. Denosumab: therapy targeted at the RANKL/OPG system Not approved by FDA yet
  45. 46. Mechanism of action Denosumab Osteoclast precursor Osteoblast Denosumab Humanized anti-RANK-Ligand RANK OPG RANK -Ligand
  46. 47. <ul><li>7,868 women ages 60 to 90 </li></ul><ul><li>Mean L-spine T-score -2.8 </li></ul><ul><li>23% of had prevalent vertebral fractures at baseline </li></ul><ul><li>60 mg of denosumab subQ every six months or placebo for 3 years </li></ul><ul><li>68% reduction in vertebral fractures p<0.0001. </li></ul><ul><li>20% reduction in non-vertebral fractures p=0.011. </li></ul><ul><li>40% reduction in hip fracture at p=0.036. </li></ul><ul><li>No increased incidence of malignancy </li></ul><ul><li>Some increase in erysipelas </li></ul>Denosumab: The FREEDOM trial
  47. 48. Targeting the bone formation side of the bone remodeling cycle
  48. 49. Parathyroid Hormone
  49. 50. PTH - Mechanism of Action PTH binds to cell surface G protein-coupled receptor Decreased apoptosis and stimulation of osteoblasts Stimulation of differentiation of proosteoblasts to osteoblasts Net increase in number and action of bone forming osteoblasts
  50. 51. Effect of rhPTH(1-34) on the Risk of New Vertebral Fractures * p <0.001 vs. Placebo Risk Reduction (RR) Placebo (n=448) rhPTH 20 (n=444) rhPTH 40 (n=434) 64 22 19 100% 75% 50% 0% 25% % of Women 8 0 2 4 6 10 12 14 65% 69% No. of women who had > 1 fracture RR 0.31 (95% CI, 0.19 to 0.50)* RR 0.35 (95% CI, 0.22 to 0.55)*
  51. 52. PTH plus ALENDRONTE may not be better than PTH alone
  52. 53. PTH <ul><li>Advantages </li></ul><ul><ul><li>First anabolic therapy </li></ul></ul><ul><ul><li>Good efficacy data </li></ul></ul><ul><li>Use first prior to bisphosphate </li></ul><ul><li>18 months – 2 years treatment </li></ul>
  53. 54. PTH <ul><li>Disadvantages </li></ul><ul><ul><li>Must be given by subcutaneous injection </li></ul></ul><ul><ul><li>Risk Osteosacroma </li></ul></ul><ul><ul><li>Cost </li></ul></ul><ul><li>Monitoring </li></ul><ul><ul><li>Hypercalcemia and hypercalciuria </li></ul></ul><ul><ul><li>Check one week and then six months after initiation treatment </li></ul></ul><ul><li>Not use in patients with calcium oxalate renal stone disease </li></ul>
  54. 55. Summary <ul><li>Osteoporosis is an important public health problem </li></ul><ul><li>Accurate diagnosis and treatment requires the use of bone </li></ul><ul><li>densitometry. </li></ul><ul><li>Radiologists play a central role in the diagnosis and management </li></ul><ul><ul><li>of this disease: </li></ul></ul><ul><ul><li>measuring bone density </li></ul></ul><ul><ul><li>diagnosing fractures </li></ul></ul><ul><ul><li>pointing out secondary causes of bone loss </li></ul></ul><ul><li>There needs to be greater attention paid to fall risk-reduction and other modifiable environmental factors. </li></ul>
  55. 56. Summary <ul><li>A variety or antiresorptive agents are available for the prevention and treatment of osteoporosis of which the bisphosphonates are the most efficacious. </li></ul><ul><li>Parathyroid hormone is the 1st truly anabolic therapy for the treatment of osteoporosis and is an important addition to our therapeutic regimen. </li></ul><ul><li>Additional anabolic therapies are on the horizon </li></ul>
  56. 57. Thank you for your attention

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