Treatment of Postmenoapausal Osteoporosis

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Treatment ofPostmenoapausalOsteoporosis
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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
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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
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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

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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

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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

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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
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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
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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
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Osteoporosis - Risk factors

• Endocrine disease
• primary hyperparathryroidism
• thyrotoxicosis
• Cushings syndrome
• Addisons disease
• Rheumatologic diseases
• rheumatoid arthritis
• ankylosing spondylitis

N Engl J Med 1998338736-746
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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
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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
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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
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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
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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
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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
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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
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Pathophysiology remodeling space

• differential effects
• cancellous-bone loss
• estrogen deficiency
• glucocorticoid therapy
• cortical bone loss
• parathyroid hormone excess

N Engl J Med 1998338736-746
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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
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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
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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
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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
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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
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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
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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
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Current Therapiesbiphosphonates

• Risedronate 2.5 - 5.0 mg/day
• (Actonel)
• decreased spine fractures by 40 to 50
• no significant reduction in hip fractures

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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
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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
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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
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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
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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
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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
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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
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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