Transcript Pm-osp

Treatment of
Postmenoapausal
Osteoporosis
3/98
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1
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)
• 1:2 women and 1:8 men are affected
• progression is slow, silent, painless
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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
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Osteoporosis Int 1997;7:1-6
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Osteoporosis - definition
“a bone mineral density (T score) that
is 2.5 SD below the mean peak value
in young adults”
Working Group of the W.H.O.
• useful for research but limited in clinical use
– ignores other determinants of bone strength
– ignores higher risk of fracture in older women
– failed to specify technique and site of measurement
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J Bone Miner Res 1994; 9:1137-41
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Bone mineral density
Z 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
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N Engl J Med 1998;338:736-746
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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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Osteoporosis
clinical risk factors
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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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Osteoporosis
clinical risk factors
National Osteroporosis Foundation
• low body weight (<58 kg)
• current smoking
• first-degree relative with low-trauma
fracture
• personal history of low-trauma fracture
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Osteoporosis Int (in press)
N Engl J Med 1998;338:736-746
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Osteoporosis - Risk factors
• Genetic factor
– first-degree relative with low-trauma fracture
• Environmental factors
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–
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cigarette smoking
alcohol abuse
physical inactivity
thin habitus
diet low in calcium
little exposure to sunlight
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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
–
–
–
–
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glucocorticoids (  7.5 mg/day for > 6 months)
antiepileptic drugs (e.g., phenytoin)
excessive substitution therapy (e.g., thyroxine)
anticoagulant drugs (e.g., heparin, warfarin)
N Engl J Med 1998;338:736-746
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Osteoporosis - Risk factors
• Endocrine disease
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–
–
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primary hyperparathryroidism
thyrotoxicosis
Cushing’s syndrome
Addison’s disease
• Rheumatologic diseases
– rheumatoid arthritis
– ankylosing spondylitis
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Osteoporosis - Risk factors
• Hematologic disease
–
–
–
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myltiple myeloma
systemic mastocytosis
lymphoma, leukemia
pernicious anemia
• Gastrointestinal diseases
– malabsorption syndromes (e.g., celiac disease,
Crohn’s disease, surgery for peptic ulcer)
– chronic liver disease (primary biliary cirrhosis)
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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)
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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
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Diagnostic Evaluation
bone mineral density
• Diagnosis and treatment
– T score < -2.5
need treatment to prevent fractures
– T score < -2 ( at any site)
indicates accelerated bone loss
need to identify major risk factor
– T score < -1 (lumbar spine or prox
femur) need to prevent further bone
loss
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Diagnostic Evaluation
biochemical markers
• Bone formation
– serum alkaline phosphatase
– serum ostocalcin
– serum C- and N-propeptides of type I
collagen
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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
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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
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Pathophysiology
remodeling space
• differential effects
• cancellous-bone loss
– estrogen deficiency
– glucocorticoid therapy
• cortical bone loss
– parathyroid hormone excess
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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%
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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
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Effective of Drug Therapy on
Lumbar-Spine Bone Marrow Density
1.2
Bone Formation drug
1.1
Antiresorptive drug
1.0
Placebo
0.9
-1
0
1
2
3
4
Year
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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
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Effects of Therapy on Lumbar-Spine
BMD and Rate of Vertebral Fracture
14
12
10
8
6
4
2
Sodium fluoride
Alendronate
Estradioal
0
-4
-3
-2
-1
0
1
2
Lumbar-Spine Bone Mineral Density
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Current Therapies
estrogen-replacement
• Benefits
– 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
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Current Therapies
estrogen-replacement
• Risks
– return of menstrual bleeding
– risk of endometrial carcinoma
– breast tenderness
– risk of breast carcinoma
– migraine
– risk of DVT and pulmonary embolism
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Current Therapies
biphosphonates
• Stable analogues of pyrophosphate
• poorly absorbed from the intestine
(<10%), 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
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Current Therapies
biphosphonates
Etidronate
low dose intermittent therapy:
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
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Current Therapies
biphosphonates
Alendronate
10 mg per day
• 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
• associated with erosive esophagitis
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Current Therapies
biphosphonates
Alendronate
• to minimize the risk of esophagitis take with a glass of water while upright
at least 30 minutes before breakfast
• absolute contraindications: achalasia,
esophageal strictures
• relative contraindications: reflux disease
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Current Therapies
calcium 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
3/98
BMJ 1994;308:1081-2
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Current Therapies
calcium 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
3/98
Ann Intern Med 1996;124:400-6
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Current Therapies
calcium and vitamin D
• U.S. Study
– 389 men and women over age >63
– 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%)
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N Engl J Med 1997;337:70-6
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Current Therapies
calcitonin
• a 32-amino-acid peptide produced by
the thyroid C cells
• inhibits the action of ostoclasts
• decreases bone resorption
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Current Therapies
calcitonin
• 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
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Current Therapies
fluoride
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
3/98
Ostoporosis Int (in press)
N Engl J Med 1997;337:70-6
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Future Treatments
• Estrogen-receptor modulators
– has mixed estrogen-agonist and estrogenantagonist activity
– raloxifene * shown to decrease bone
resorption and increase BMD in the lumbarspine (2.4%), hip (2.4%), and body (2.0%)
– Others: tamoxifen, drolxifene,
levormeloxifene
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J Bone Miner Res 1996;11:835-42
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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
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J Clin Endocrinol Metab 1997;82:620-8
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Conclusions
Therapeutic 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
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Conclusions
Therapeutic 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)
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Conclusions
Therapeutic 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
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Conclusions
Therapeutic Goal
• to halve the risk of fracture
• a new fracture should not be considered
a set back
• patients should be encouraged to
continue therapy
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References
•
•
•
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Treatment of Postmenopausal Osteoporosis.
Richard Eastell, MD. N Engl J Med 1998;338:736-746
Effect of calcium and cholecalciferol treatment for three years on hip
fractures in elderly women.
Chapuy MC et al. BMJ 1994;308:1081-2
Vitamin D supplementation and fracture incidence inelderly persons.
Lips P et al. Ann Inern Med 1996;124:400-6
medslides.com 44