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Treatment of Postmenoapausal Osteoporosis

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A disease that causes bones to lose mass, weaken and fracture ... malabsorption syndromes (e.g., celiac disease, Crohn's disease, surgery for peptic ulcer) ... – PowerPoint PPT presentation

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Title: Treatment of Postmenoapausal Osteoporosis


1
Treatment ofPostmenoapausalOsteoporosis
2
What is Osteoporosis
  • A disease that causes bones to lose mass, weaken
    and fracture
  • affects 75 million people in Europe, Japan and
    the United States (over 28 million Americans)
  • 12 women and 18 men are affected
  • progression is slow, silent, painless

3
Osteoporosis - definition
  • a systemic skeletal disease characterized by
    low bone mass and microarchitectural
    deterioration with a consequent increase in bone
    fragility and susceptibility to fracture
  • Consensus Development Conference

Osteoporosis Int 199771-6
4
W.H.O. Working Group
  • a bone mineral density (T score) that is 2.5 SD
    below the mean peak value in young adults
  • osteopenia - T score between -1 and -2.5
  • osteoporosis - T score lt -2.5
  • severe osteoporosis - T score lt -2.5 with a
    fracture

J Bone Miner Res 1994 91137-41
5
Bone mineral densityZ Score
  • Z score - a comparison with the mean value in
    normal subjects of the same age and sex (either
    at the lumbar spine or the proximal femur)
  • Z score below -1 (lowest 25)risk of fracture is
    approx doubled
  • Z score below -2 (lowest 2.5)risk of fracture
    is even higher

N Engl J Med 1998338736-746
6
Bone Development
  • Bones build mass beginning at birth and peaks by
    age 20-30
  • bone growth promoted by adequate intake of
    calcium, vitamin D, and exercise
  • bone begin to lose mass after age 30

7
Building Strong Bones
  • Adequate calcium intake
  • teenagers and postmenopasal women not taking
    estrogen need 1,500 mg of calcium per day
  • other adults need 1,000 mg per day
  • Vitamin D
  • Adequate exercise

8
Osteoporosisclinical risk factors
  • Female gender
  • Caucasian or Asian race
  • Thin body build
  • Late onset of menstrual periods
  • Early onset menopause
  • Caffeine, Cigarettes and Alcohol
  • A family history of osteoporosis

9
Osteoporosisclinical risk factors
  • National Osteroporosis Foundation
  • low body weight (lt58 kg)
  • current smoking
  • first-degree relative with low-trauma fracture
  • personal history of low-trauma fracture

Osteoporosis Int (in press) N Engl J Med
1998338736-746
10
Osteoporosis - Risk factors
  • Genetic factor
  • first-degree relative with low-trauma fracture
  • Environmental factors
  • cigarette smoking
  • alcohol abuse
  • physical inactivity
  • thin habitues
  • diet low in calcium
  • little exposure to sunlight

N Engl J Med 1998338736-746
11
Osteoporosis - Risk factors
  • Menstral status
  • early menopause (before the age of 45 years)
  • previous amenorrhea (e.g., due to anorexia
    nervosa, hyperprolactinemia)
  • Drug therapy
  • glucocorticoids ( ? 7.5 mg/day for gt 6 months)
  • antiepileptic drugs (e.g., phenytoin)
  • excessive substitution therapy (e.g., thyroxine)
  • anticoagulant drugs (e.g., heparin, warfarin)

N Engl J Med 1998338736-746
12
Osteoporosis - Risk factors
  • Endocrine disease
  • primary hyperparathryroidism
  • thyrotoxicosis
  • Cushings syndrome
  • Addisons disease
  • Rheumatologic diseases
  • rheumatoid arthritis
  • ankylosing spondylitis

N Engl J Med 1998338736-746
13
Osteoporosis - Risk factors
  • Hematologic disease
  • myltiple myeloma
  • systemic mastocytosis
  • lymphoma, leukemia
  • pernicious anemia
  • Gastrointestinal diseases
  • malabsorption syndromes (e.g., celiac disease,
    Crohns disease, surgery for peptic ulcer)
  • chronic liver disease (primary biliary cirrhosis)

N Engl J Med 1998338736-746
14
Diagnostic Evaluation bone mineral density
  • indications
  • in women with strong risk factors(see slides
    10-13)
  • in those with osteoporosis-related fractures
    (wrist, spine, proximal femur, or humerus after
    mild or moderate trauma)

N Engl J Med 1998338736-746
15
Diagnostic Evaluation bone mineral density
  • techniques
  • dual-energy x-ray absorptiometry (DEXA)
  • proximal femur is most useful for predicting
    fractures
  • lumbar spine is most useful for monitoring
    therapy
  • single-energy x-ray absorptiometry
  • quantitative computed tomography
  • ultrasonography

N Engl J Med 1998338736-746
16
Treatment RecommendationsThe National
Osteoporosis Foundation
  • T score lt -2.0
  • treatment with an antiresorptive agent to prevent
    fractures
  • T score lt -1.5 to -2.0
  • treatment with any of the following risk factors
  • family history of osteoporosis
  • previous fracture
  • current tobacco use
  • body weight lt 127 pounds

National Osteoporosis Foundation, 19988
17
Diagnostic Evaluation biochemical markers
  • Bone formation
  • serum alkaline phosphatase
  • serum ostocalcin
  • serum C- and N-propeptides of type I collagen

N Engl J Med 1998338736-746
18
Diagnostic Evaluation biochemical markers
  • Bone resorption
  • urinary excretion of
  • pyridium cross-links of collagen
    (deoxypyridinoline)
  • C- and N-telopeptides of collagen
  • galactosyl hydroxylysine
  • hydroxyproline
  • serum tartrate-resistant acid phosphatase

N Engl J Med 1998338736-746
19
Pathophysiology remodeling space
  • space where some bone has been resorbed but not
    yet replaced during the remodeling process
  • remodeling space is increased in postmenopausal
    osteoporosis

N Engl J Med 1998338736-746
20
Pathophysiology remodeling space
  • differential effects
  • cancellous-bone loss
  • estrogen deficiency
  • glucocorticoid therapy
  • cortical bone loss
  • parathyroid hormone excess

N Engl J Med 1998338736-746
21
Antiresorptive Drugs
  • antiresorptive drugs (estrogen, bisphosphonates,
    calcitonin) ? both the rates of bone resorption
    (in weeks) and formation (in months)
  • bone mineral density is ? by 5-10 for the first
    2-3 years then plateaus this reduces the risk of
    fracture by 50

N Engl J Med 1998338736-746
22
Bone Formation Drugs
  • sodium fluoride and intermittent parathyroid
    hormone
  • stimulate bone formation
  • overfill resorption cavities
  • the increase in bone density continues beyond two
    years

N Engl J Med 1998338736-746
23
Effective of Drug Therapy onLumbar-Spine Bone
Marrow Density
1.2
Bone Formation drug
1.1
Lumbar-Spine Bone Mineral Density (g/cm2)
Antiresorptive drug
1.0
Placebo
0.9
-1 0 1 2 3 4 Year
N Engl J Med 1998338736-746
24
Risk Factors for Bone Fracture
  • ? bone marrow density (BMD)
  • high rate of bone turnover - the site of
    remodeling can break
  • type of drug therapy - e.g., sodium fluoride
    increases BMD, but weakens the bone by being
    incorporated into the hydroxyapatite crystals of
    bone

N Engl J Med 1998338736-746
25
Effects of Therapy on Lumbar-Spine BMD and Rate
of Vertebral Fracture
14
12
10
8
Relative Risk of Vertebral Fracture
6
Sodium fluoride
4
Alendronate
2
Estradioal
0
-4 -3 -2 -1 0 1
2Lumbar-Spine Bone Mineral Density
N Engl J Med 1998338736-746
26
Current Therapiesestrogen-replacement
  • Benefits (no prospective studies)
  • relief of menopausal symptoms
  • prevention of bone loss and fractures
  • increase in bone marrow density
  • decrease in bone turn over
  • lower relative risk (0.39) for vertebral fracture
  • prevention of ischemic heart disease
  • prevention of dementia

N Engl J Med 1998338736-746
27
Current Therapiesestrogen-replacement
  • Risks
  • return of menstrual bleeding
  • risk of endometrial carcinoma
  • breast tenderness
  • risk of breast carcinoma
  • migraine
  • risk of DVT and pulmonary embolism

N Engl J Med 1998338736-746
28
Current Therapiesselective estrogen receptor
modulator
  • Raloxifene 60 mg/day
  • (Evista)
  • reduced the incidence of spine fracture by 30 in
    3 years
  • no significant reduction in nonvertebral or hip
    fractures

N Engl J Med 1998338736-746
29
Current Therapiesbiphosphonates
  • Stable analogues of pyrophosphate
  • poorly absorbed from the intestine (lt10), must
    not be taken with food
  • deposited in bone at the site of mineralization
    apparently causing the death of osteoclasts which
    results in decreased bone resorption

N Engl J Med 1998338736-746
30
Current Therapiesbiphosphonates
  • Etidronate low dose intermittent therapy
  • (Didronel) 400 mg /day x 2 wks,
    followed by 500 mg supplemental calcium
  • per day x 11 wks
  • increase in BMD of 4-8 in lumbar spine and 2 in
    femoral neck in 3 yrs
  • decrease in vertebral fracture rate

N Engl J Med 1998338736-746
31
Current Therapiesbiphosphonates
  • Alendronate 5 - 10 mg per day
  • (Fosamax)
  • the only medication that has unequivocally been
    shown to reduce the risk of hip fracture in
    prospective studies
  • increase in BMD of 8.8 in lumbar spine and 5.9
    in femoral neck in 3 yrs
  • 48 relative decrease in new fractures and height
    loss

N Engl J Med 1998338736-746
32
Current Therapiesbiphosphonates
  • Alendronate
  • associated with erosive esophagitis - to
    minimize the risk, take with a full glass of
    water, while upright, at least 30 minutes before
    breakfast
  • absolute contraindications achalasia, esophageal
    strictures
  • relative contraindications reflux disease

N Engl J Med 1998338736-746
33
Current Therapiesbiphosphonates
  • Risedronate 2.5 - 5.0 mg/day
  • (Actonel)
  • decreased spine fractures by 40 to 50
  • no significant reduction in hip fractures

34
Current Therapiescalcium and vitamin D
  • French Study
  • 3270 institutionalized women
  • treated with calcium (1200 mg per day) and
    vitamin D (800 IU per day) for 3 yrs
  • risk of hip fracture was reduced by 30
  • reversal of secondary hyperparathyroidism
  • increase in BMD of the femoral neck

BMJ 19943081081-2
35
Current Therapiescalcium and vitamin D
  • Dutch Study
  • 2578 elderly women
  • treated with vitamin D (400 IU per day)but no
    supplemental calcium
  • rate of hip fracture unchanged compared to
    placebo
  • comment the women were not housebound

Ann Intern Med 1996124400-6
36
Current Therapiescalcium and vitamin D
  • U.S. Study
  • 389 men and women over age gt63
  • treated with calcium (500 mg per day) and vitamin
    D (700 IU per day)
  • decreased rate of nonvertebral fractures with
    only a small increase in BMD of the lumbar spine
    (0.9), femoral neck (1.2), and total body
    (1.2)

N Engl J Med 199733770-6
37
Current Therapiescalcitonin
  • a 32-amino-acid peptide produced by the thyroid C
    cells
  • inhibits the action of ostoclasts
  • decreases bone resorption

N Engl J Med 199733770-6
38
Current Therapiescalcitonin
  • Salmon or human calcitonin
  • 100 IU daily, subcutaneous or intramuscular
  • 200 IU daily, intranasal (salmon calcitonin)
  • suppositories are weak and poorly tolerated
  • Benefits
  • increase BMD, decrease vertebral fracture
  • Side effects
  • nausea, flushing, diarrhea, nasal discomfort

N Engl J Med 199733770-6
39
Current Therapiesfluoride
  • Fluoride Vertebral Osteoporosis Study
  • 354 women with osteoporosis
  • 2 year trial of sodium fluoride (50 mg/d) vs
    placebo
  • significant increase in lumbar-spine BMD (10.8
    vs 2.4), but no effect on the rate of vertebral
    fracture

Ostoporosis Int (in press) N Engl J Med
199733770-6
40
Future Treatments
  • selective estrogen-receptor modulators
  • has mixed estrogen-agonist and estrogen-antagonist
    activity
  • raloxifene shown to decrease bone resorption
    and increase BMD in the lumbar-spine (2.4), hip
    (2.4), and body (2.0)
  • Others tamoxifen, drolxifene, levormeloxifene

J Bone Miner Res 199611835-42
41
Future Treatments
  • Parathyroid Hormone
  • daily injections stimulate bone formation
  • increase in BMD of the spine
  • effects on fracture rate not yet known
  • Vitamin D analogues
  • strontium salts
  • ipriflavone

J Clin Endocrinol Metab 199782620-8
42
ConclusionsTherapeutic Choices
  • Women most at risk should be treated
  • fracture with minimal or no trauma
  • those with low bone marrow density
  • Acute phase of vertebral fracture
  • manage with analgesic drugs
  • lumbar-support corset
  • short period of bed rest and calcitonin

N Engl J Med 199733770-6
43
ConclusionsTherapeutic Choices
  • Life style change
  • avoid heavy lifting
  • encourage exercise (such as walking)
  • avoid sedative drugs (may cause falls)
  • calcium intake increase to 1500 mg / day
  • avoid tobacco and excess alcohol
  • hip protectors (poor compliance)

N Engl J Med 199733770-6
44
ConclusionsTherapeutic Choices
  • first choice
  • estrogen-replacement therapy should be given for
    at least 5 years
  • use preparation that do not cause uterine bleed
    (continuous combined estro-progest)
  • alternative choice
  • biphosphonates (avoid SE of estrogen)
  • vitamin D for housebound patients

N Engl J Med 199733770-6
45
ConclusionsTherapeutic Goal
  • to halve the risk of fracture
  • a new fracture should not be considered a set
    back
  • patients should be encouraged to continue therapy

N Engl J Med 199733770-6
46
References
  • Treatment of Postmenopausal Osteoporosis.Richard
    Eastell, MD. N Engl J Med 1998338736-746
  • Effect of calcium and cholecalciferol treatment
    for three years on hip fractures in elderly
    women.Chapuy MC et al. BMJ 19943081081-2
  • Vitamin D supplementation and fracture incidence
    inelderly persons. Lips P et al. Ann Inern Med
    1996124400-6
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