Treatment of Postmenoapausal Osteoporosis

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Treatment ofPostmenoapausal

Osteoporosis


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


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 1997;7:1-6


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

J Bone Miner Res 1994; 9:1137-41


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 1998;338:736-746


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


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


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


Osteoporosisclinical 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

Osteoporosis Int (in press)N Engl J Med 1998;338:736-746


Osteoporosis - Risk factors

• Genetic factor– first-degree relative with low-trauma fracture

• Environmental factors– cigarette smoking– alcohol abuse– physical inactivity– thin habitus– diet low in calcium– little exposure to sunlight

N Engl J Med 1998;338:736-746



• 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 > 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



• Endocrine disease– primary hyperparathryroidism– thyrotoxicosis– Cushing’s syndrome– Addison’s disease

• Rheumatologic diseases– rheumatoid arthritis– ankylosing spondylitis

N Engl J Med 1998;338:736-746



• Hematologic disease– 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)

N Engl J Med 1998;338:736-746


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 1998;338:736-746



• 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 1998;338:736-746



• Diagnosis and treatment– T score < -2.5

need treatment to prevent fractures– T score < -2 ( at any site)

indicates accelerated bone lossneed to identify major risk factor

– T score < -1 (lumbar spine or prox femur) need to prevent further bone loss

N Engl J Med 1998;338:736-746


Diagnostic Evaluation biochemical markers

• Bone formation– serum alkaline phosphatase– serum ostocalcin– serum C- and N-propeptides of type I

collagen

N Engl J Med 1998;338:736-746


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 1998;338:736-746


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 1998;338:736-746


Pathophysiology remodeling space

• differential effects

• cancellous-bone loss– estrogen deficiency– glucocorticoid therapy

• cortical bone loss– parathyroid hormone excess

N Engl J Med 1998;338:736-746


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 1998;338:736-746


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 1998;338:736-746


Effective of Drug Therapy onLumbar-Spine Bone Marrow Density

Placebo

Antiresorptive drug

Bone Formation drug

-1 0 1 2 3 4Year

0.9

1.0

1.1

1.2

N Engl J Med 1998;338:736-746

Lu

mb

ar-S

pin

e B

one

Min

eral

Den

sity

(g/

cm2 )


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 1998;338:736-746


Effects of Therapy on Lumbar-Spine BMD and Rate of Vertebral Fracture

Sodium fluorideAlendronate

-4 -3 -2 -1 0 1 2Lumbar-Spine Bone Mineral Density

Rel

ativ

e R

isk

of

Ver

teb

r al F

r ac t

ure

0

2

4

6

8

10

12

14

Estradioal

N Engl J Med 1998;338:736-746


Current Therapiesestrogen-replacement

N Engl J Med 1998;338:736-746

• 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


Current Therapiesestrogen-replacement

N Engl J Med 1998;338:736-746

• Risks– return of menstrual bleeding– risk of endometrial carcinoma– breast tenderness– risk of breast carcinoma– migraine– risk of DVT and pulmonary embolism


Current Therapiesbiphosphonates

N Engl J Med 1998;338:736-746

• 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



N Engl J Med 1998;338:736-746

Etidronate low dose intermittent therapy:

400 mg /day x 2 wks, followedby 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 1998;338:736-746

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



N Engl J Med 1998;338:736-746

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


Current Therapiescalcium and vitamin D

BMJ 1994;308:1081-2

• 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



Ann Intern Med 1996;124:400-6

• 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



N Engl J Med 1997;337:70-6

• 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%)


Current Therapiescalcitonin

N Engl J Med 1997;337:70-6

• a 32-amino-acid peptide produced by the thyroid C cells

• inhibits the action of ostoclasts

• decreases bone resorption


Current Therapiescalcitonin

N Engl J Med 1997;337:70-6

• 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


Current Therapiesfluoride

Ostoporosis Int (in press)N Engl J Med 1997;337:70-6

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


Future Treatments

J Bone Miner Res 1996;11:835-42

• 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


Future Treatments

J Clin Endocrinol Metab 1997;82:620-8

• 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


ConclusionsTherapeutic Choices

N Engl J Med 1997;337:70-6

• 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 1997;337:70-6

• 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 1997;337:70-6

• 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


ConclusionsTherapeutic Goal

N Engl J Med 1997;337:70-6

• to halve the risk of fracture

• a new fracture should not be considered a set back

• patients should be encouraged to continue therapy


References

• 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

Treatment of Postmenoapausal Osteoporosis

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