Osteoporosis

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Osteoporosis

• Seki A. Balogun, MD
• Assistant Professor of Clinical Internal Medicine
• Division of General Medicine, Geriatrics and
  Palliative Care

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Introduction

• Most common bone disease
• Major risk factor for fracture

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Definition

• A systemic skeletal disease characterized by 2
  main elements
• low bone mass
• microarchitectural deterioration of bone tissue
  with a consequent increase in bone fragility and
  susceptibility to fracture
• bone present is normally mineralized

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Epidemiology

• Affects 24 million in USA
• Contributes to 1.3 million fractures/yr
• 50 of these fractures are vertebral fractures,
  25 are hip fractures, and 25 are Colles
  fractures
• 10-15 billion/yr. for hip fractures
• Estimated cost of osteoporotic fractures in the
  United States in 1995 was 13.8 billion

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MECHANISMS OF OSTEOPOROSIS

• High turnover excessive bone resorption gt
  excessive bone formation
• - estrogen deficiency (menopause)
• - hypogonadism (testosterone deficiency)
• - hyperparathyroidism
• - hyperthyroidism
• Low turnover decreased bone formation
  gtdecreased bone resorption
• - liver disease (primarily primary biliary
  cirrhosis)
• - heparin
• - alcoholism
• Increased bone resorption and decreased bone
  formation
• - Glucocorticoids

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PATHOGENESIS ROLE OF SYSTEMIC HORMONES

• Calcium-regulating hormones Calcitonin,
  parathyroid hormone, Vitamin D
• Estrogen - inhibits bone resorption
• deficiency (menopause) - increased bone
  resorption and rapid bone loss.
• Androgens - deficiency results in bone loss with
  increased bone turnover similar to estrogen
  deficiency
• Growth hormone/insulin-like growth factor - major
  determinant of skeletal growth
• small role in most cases of osteoporosis

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PATHOGENESISLOCAL CYTOKINES AND PROSTAGLANDINS

• Cytokines - IL-I , IL-6 and TNF-a - potent
  stimulators of bone resorption and can also
  inhibit bone formation.
• - IL-4 and IL-13 inhibit bone resorption
• Prostaglandins particularly E2, increase both
  bone resorption and formation
• - many of the local and systemic factors that
  regulate bone metabolism also affect
  prostaglandin synthesis in bone
• Local Growth factors - IGFs - important in
  maintaining the differentiation and function of
  osteoblasts
• - Others TGF-beta, PTHrP, Fibroblast growth
  factor

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RISK FACTORS FOR OSTEOPOROSIS

• AGE
• Bone mass decreases with age
• Age-related bone loss begins in the 4th or 5th
  decades
• slow loss of cortical and trabecular bone in
  both men and women
• Fracture risk also increases with age
• Decreased calcium and vitamin D intake and
  reduced sun exposure can lead to secondary
  hyperparathyroidism, which may play a role in
  age-related bone loss

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Risk Factors

• SEX
• More common in women
• Overall fracture rate increased threefold in
  women
• Lower mean peak bone mass
• Accelerated bone loss after menopause
• About 75 percent of bone lost after menopause may
  be related to estrogen deficiency rather than age
  

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Risk Factors

• RACE
• Risk of hip fractures is lower in
  African-American women than in Caucasians
• - higher peak bone mass
• - slower rate of bone loss after menopause
• Asian women have a lower risk of fracture than
  Caucasian women.
• Though, bone mineral density is lower in Asian
  women - ? due to their smaller body habitus
• Differences in fracture risk across different
  ethnic groups cannot be explained on the basis of
  differences in bone mineral density alone

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Risk Factors

• GENETICS
• Play a contributory role in bone density and
  fracture risk
• Vitamin D receptor genotypes may affect the
  ability to bind vitamin D
• Variants in BMP2 gene identified in families
  with osteoporosis
• Variants of estrogen receptor alpha and beta
  (ESR1 and ESR2) gene

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Risk Factors

• Sedentary life style (decreased bone mass and
  physical functioning)
• Slender habitus
• Low peak bone density
• Hypogonadism
• Pregnancy and Lactation (transient loss)
• Pernicious anemia - suppression of osteoblast
  activity

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Risk Factors

• Medications steroids, excess thyroid hormone,
  methotrexate, heparin, anticonvulsants,
  cyclosporine
• Homocystinuria and high homocysteine levels in
  adults
• VitB12 and folate supplementation in older adults
  with high homocysteine level after a stroke has
  been shown to decrease hip fractures (absolute
  risk reduction 7 at 2 years)

Sato Y et al. JAMA 2005 Mar 2293(9)1082-8.
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RISK FACTORS - NUTRITION

• Calcium deficiency
• Vitamin D deficiency
• Protein excess or deficiency
• Phosphoric acid excess
• Cigarette Smoking (increases bone loss and
  decreases intestinal calcium absorption)
• Excessive caffeine intake
• Vitamin A excess

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DISEASES ASSOCIATED WITH OSTEOPENIA

• PTH
• Hyperthyroidism
• Cushings
• Myeloma
• Mastocytosis
• Liver disease
• Renal disease

• Celiac disease
• R.A.
• Osteogenesis imperfecta
• AIDS
• IBS
• Others

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Protective factors

• higher body mass index
• black race
• estrogen
• diuretic therapy (thiazides)
• exercise
• Moderate alcohol ingestion (associated with
  increased bone mineral density), data relating to
  fracture risk - mixed

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SYMPTOMS OF OSTEOPOROSIS

• Asymptomatic
• Pain with fracture (or not)
• Decreased height
• Dowagers hump- kyphosis
• Look for risk factors
• symptoms and signs of associated conditions

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LIFETIME FRACTURE RISK OF 50 YEAR OLD WOMAN

• Any fracture54
• Hip-18 (rises to 33 by age 90)
• Vertebra-35
• Colles-17

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HIP FRACTURES

• 350,000/year
• 30 of all fracture related hospitalizations
• gt4 die during hospitalization
• 10-35 die during next year
• 50 do not reach their previous level of function
• considerable morbidity and mortality
• High risk for second fracture

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LABORATORY EVALUATION

• To exclude secondary causes of osteoporosis
• Calcium, phosphorus, BUN, Cr., TSH, CBC, alkaline
  phosphatase
• Consider
• PTH, serum 25-hydroxyvitamin D levels -
  secondary hyperparathyroidism
• SPEP, UPEP multiple myeloma
• In men, serum free testosterone

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DIAGNOSIS OF OSTEOPOROSIS

• PLAIN RADIOGRAPHS
• Detectable changes with 30-50 bone loss
• Trabecular thinning
• Compression fractures
• BONE DENSITOMETRY
• Single-photon absorptiometry screening, used at
  peripheral sites (radius, calcaneus)
• Dual x-ray absorptiometry (DEXA) -GOLD STANDARD,
  precise measurements at hip and spine
• OTHER METHODS Quantitative computed tomography,
  Ultrasound

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WHO Diagnostic Criteria for Osteopenia and
Osteoporosis Based on Bone Mass Measurements

• Category
• Normal
• Osteopenia
• Osteporosis

• Bone mass
• BMD within one standard deviation of the young
  adult reference mean (T-score)
• BMD between 1- 2.5 standard deviations below the
  young adult reference mean
• BMD gt2.5 standard deviations below the young
  adult reference mean or presence of gt one
  fragility fractures

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Indications for bone densitometry

• Estrogen-deficient women at clinical risk of
  osteoporosis
• Vertebral abnormalities
• Long-term steroid use
• Primary hyperparathyroidism
• Monitoring response to therapy
• Every 2 years (controversial)

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NOF TREATMENT GUIDELINES

• Postmenopausal women with vertebral or hip
  fractures
• T-score less than 2 with no risk factors
• T-score 1.5 or below with risk factors

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TREATMENT OF OSTEOPOROSIS

• NON- PHARMACOLOGIC THERAPY
• Diet - Calcium and Vit D
• Exercise
• Smoking cessation
• PHARMACOLOGIC THERAPY (postmenopausal with
  osteopenia or osteoporosis)
• Estrogens
• Bisphosphonates
• Selective estrogen receptor modulators
• Calcitonin
• Parathyroid hormone
• Others Isoflavones, thiazide, tibolone

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CALCIUM AND VITAMIN D

• For post menpausal women and older men Daily
  calcium intake 1500mg/day
• Shown to decrease fracture rate in
  institutionalized and community elderly
• Safe except in those with other causes of
  hypercalcemia
• Probably does not increase risk of kidney stones.
• Take calcium carbonate with food for absorption
• Ca supplementation may favorably affect serum
  lipids

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VITAMIN D

• Important for calcium absorption, affects PTH
• Elderly need moreless response to sunlight, less
  efficient hydroxylation
• Total Vit D 800 IU/day
• higher doses may be required with malabsorption
  or certain meds - anticonvulsants

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Exercise and Smoking Cessation

• EXERCISE
• Associated with lower risk of hip fractures
• - increased muscular strength
• Associated with improvements in bone density
• 2 6
• Recommended exercise 30mins, 3 days/week
• SMOKING CESSATION
• Accelerates bone loss
• One pack/day in adult life associated in 5- 10
  reduction in bone density

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ESTROGENS

• Anti-resorptive, can stop bone loss and decrease
  fractures
• Was considered primary therapy in postmenopausal
  women
• WHI study of estrogen and progesterone stopped
  early due to adverse effects - breast cancer,
  CAD, stroke and venous thromboembolic events
• No more effective than bisphosphonates

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Bisphosphonates

• Alendronate (fosomax) treatment dose 10mg/day
  or 70mg weekly, prevention dose 5mg/day or 35mg
  weekly
• Risedronate (actonel) treatment and prevention
  dose 5mg/day or 35mg weekly
• New - Ibandronate (Boniva) 150mg monthly dose
• Increases bone density
• Decreases vertebral and nonvertebral fractures
• Beneficial effects for at least ten years
• Bone loss after treatment is stopped
• Side effects pill-induced esophagitis,
  hypocalcemia

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Selective estrogen receptor modulators

• Raloxifene (Evista)
• Approved for prevention and treatment
• Increases BMD
• Less effective than estrogen and bisphosphonates
  (though no direct comparisons)
• No increase in breast or endometrial cancer
• Side effects venous thromboembolism

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CALCITONIN

• Intranasal daily
• Can decrease pain of acute vertebral fracture
• Well-tolerated
• Not much effect on BMD or fracture risk

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TERIPARATIDE (FORTEO)

• Parathyroid hormone
• Intermittent administration stimulates bone
  formation more than resorption
• Daily injection
• Increases bone mass and decreases fractures
  (65-70 in vertebral fractures)
• Compared to alendronate greater increase in
  spine bone density and decreased vertebral risk
• Side effects nausea, headaches, hypercalcemia
• Reserved for high risk patients daily injection,
  high cost, risk of osteosarcoma

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Vahle JL. Toxicol Pathol. 2004 Jul-Aug32(4)426-3
8.
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Others

• Isoflavones phytoestrogen
• - Commonly found in soy products
• -Conflicting results in studies
• Thiazides diuretics useful in postmenopausal
  women with HTN
• - modest decrease in bone loss
• Tibolone synthetic steroid with estrogenic,
  androgenic, progestagenic properties
• -increases bone density, has not been shown to
  decrease fracture risk
• - may increase risk of endometrial
  hyperplasia, breast cancer
• -widely used in Europe, not FDA approved

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Potential therapies

• Androgen does not appear to be superior to
  estrogen, virilizing effects
• Growth factors stimulate bone growth, useful in
  growth hormone deficiency, conflicting trial
  results with normal levels
• Statins conflicting data, observational studies
  report no effects on bone density
• - small clinical trial showed modest increase
  in forearm BMD

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Potential therapies

• Strontium ranelate - increases bone formation,
  inhibits bone resorption
• in clinical trials, increased BMD in spine
  and femur and decreased fracture.
• side effect diarrhea, not yet commercially
  available
• Folate and Vit B12 may lower fracture risk in
  elderly patients (with elevated homocysteine
  level) after a stroke

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OSTEOPOROSIS IN MEN

• Occurs at later age
• Incidence of hip fractures increases
  exponentially with age
• Mortality associated with hip fractures and other
  major fractures is higher in men
• Men are less likely to be evaluated or receive
  antiresorptive therapy after a hip fracture
• Consider serum free testosterone, SPEP, UPEP,
  PTH, 1,25(OH2)Vitamin D level or endocrine
  consult
• Bisphosphonates proven effective in men