Osteoporosis

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Osteoporosis
Robert D. Auerbach, M.D. FACOG Senior Vice
President Chief Medical Officer CooperSurgical,
Inc. Associate Clinical Professor Yale University
School of Medicine

• PATHOGENESIS
• DIAGNOSIS
• TREATMENT

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Two Components of the Bone

• Cortical Bone
• Dense and compact
• Runs the length of the long bones, forming a
  hollow cylinder
• Trabecular bone
• Has a light, honeycomb structure
• Trabeculae are arranged in the directions of
  tension and compression
• Occurs in the heads of the long bones
• Also makes up most of the bone in the vertebrae

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Osteons

• Principal organizing feature of compact bone
• Haversian canal place for the nerve blood and
  lymphatic vessels
• Lamellae collagen deposition pattern
• Lacunae holes for osteocytes
• Canaliculi place of communication between
  osteocytes

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Bone Cells

• Osteocytes - derived from osteoprogenitor cells
• Osteoblasts
• Osteoclasts

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Osteocytes

• Trapped osteoblasts
• In lacunae
• Keep bone matrix in good condition and can
  release calcium ions from bone matrix when
  calcium demands increase
• Osteocytic osteolysis

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Osteoblasts

• Make collagen
• Activate nucleation of hydroxyapatite
  crystallization onto the collagen matrix, forming
  new bone
• As they become enveloped by the collagenous
  matrix they produce, they transform into
  osteocytes
• Stimulate osteoclast resorptive activity

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Osteoclasts

• Resorb bone matrix from sites where it is
  deteriorating or not needed
• Digest bone matrix components
• Focal decalcification and extracellular digestion
  by acid hydrolases and uptake of digested
  material
• Disappear after resorption
• Assist with mineral homeostasis

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Chemistry of the Bone

• Matrix
• Mineral

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Matrix - Osteoid

• Collagen type I and IV
• Layers of various orientations (add to the
  strength of the matrix)
• Other proteins 10 of the bone protein
• Direct formation of fibers
• Enhance mineralization
• Provide signals for remodeling

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Mineral

• A calcium phosphate/carbonate compound resembling
  the mineral hydroxyapatite Ca10(PO4)6(OH)2
• Hydroxyapatite crystals
• Imperfect
• Contain Mg, Na, K

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Mineralization of the Bone

• Calcification occurs by extracellular deposition
  of hydroxyapatite crystals
• Trapping of calcium and phosphate ions in
  concentrations that would initiate deposition of
  calcium phosphate in the solid phase, followed by
  its conversion to crystalline hydroxyapatite
• Mechanisms exist to both initiate and inhibit
  calcification

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Bone Remodeling Process

• Proceeds in cycles first resorption than bone
  formation
• The calcium content of bone turns over with a
  half-life of 1-5 years

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Bone Remodeling Process
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Coordination of Resorption and Formation

• Phase I
• Signal from osteoblasts
• Stimulation of osteoblastic precursor cells to
  become osteoclasts
• Process takes 10 days

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Coordination of Resorption and Formation

• Phase II
• Osteoclast resorb bone creating cavity
• Macrophages clean up
• Phase III
• New bone laid down by osteoblasts
• Takes 3 months

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Pathways of Differentiation of Osteoclasts and
Osteoblasts
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Hormonal Influence

• Vitamin D
• Parathyroid Hormone
• Calcitonin
• Estrogen
• Androgen

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Vitamin D

• Osteoblast have receptors for (1,25-(OH)2-D)
• Increases activity of both osteoblasts and
  osteoclasts
• Increases osteocytic osteolysis (remodeling)
• Increases mineralization through increased
  intestinal calcium absorption
• Feedback action of (1,25-(OH)2-D) represses gene
  for PTH synthesis

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Parathyroid Hormone

• Accelerates removal of calcium from bone to
  increase Ca levels in blood
• PTH receptors present on both osteoblasts and
  osteoclasts
• Osteoblasts respond to PTH by
• Change of shape and cytoskeletal arrangement
• Inhibition of collagen synthesis
• Stimulation of IL-6, macrophage
  colony-stimulating factor secretion
• Chronic stimulation of the PTH causes
  hypocalcemia and leads to resorptive effects of
  PTH on bone

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Calcitonin

• C cells of thyroid gland secrete calcitonin
• Straight chain peptide - 32 aa
• Synthesized from a large preprohormone
• Rise in plasma calcium is major stimulus of
  calcitonin secretion
• Plasma concentration is 10-20 pg/ml and half life
  is 5 min

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Actions of Calcitonin

• Osteoclasts are target cells for calcitonin
• Major effect of clacitonin is rapid fall of
  plasma calcium concentration caused by inhibition
  of bone resorption
• Magnitude of decrease is proportional to the
  baseline rate of bone turnover

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Other Systemic Hormones

• Estrogens
• Increase bone remodeling
• Androgens
• Increase bone formation

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Other Systemic Hormones

• Growth hormone
• Increases bone remodeling
• Glucocorticoids
• Inhibit bone formation
• Thyroid hormones
• Increase bone resorption
• Increase bone formation

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Local Regulators of Bone Remodeling

• Cytokines
• IL-6
• IL-1
• Prostaglandins
• Growth factors
• IGF-I
• TGF-ß

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Osteoporosis

• A disease characterized by
• low bone mass
• microarchitectural deterioration of the bone
  tissue
• Leading to
• enhanced bone fragility
• increase in fracture risk

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WHO Guidelines for Determining Osteoporosis

• Normal Not less than 1 SD below the avg. for
  young adults
• Osteopenia -1 to -2.5 SD below the mean
• Osteoporosis More than 2.5 SD below the young
  adult average
• 70 of women over 80 with no estrogen replacement
  therapy qualify
• Severe osteoporosis
• More than 2.5 SD below with fractures

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Osteoporosis - Epidemiology

• Disorder of postmenopausal women of northern
  European descent
• Increase in the incidence related to decreasing
  physical activity
• Over 27 million or 1 of 3 women are affected with
  osteoporosis
• Over 5 million or 1 of 5 men are affected with
  osteoporosis

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Statistics
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Prevalence of Osteopenia and Osteoporosis in
Postmenopausal Women by Ethnicity
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Pathogenesis of Estrogen Deficiency and Bone Loss

• Estrogen loss triggers increases in IL-1, IL-6,
  and TNF due to
• Reduced suppression of gene transcription of IL-6
  and TNF
• Increased number of monocytes
• Increased cytokines lead to increased osteoclast
  development and lifespan

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Osteoclast Differentiation and Activation in
Estrogen Deficiency
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Impact of Estrogen on Osteoclastic
Differentiation and Activation
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National Osteoporosis Risk Assessment (NORA)
Factors Associated With Increased Risk of
Osteoporosis
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NORA Factors Associated With Reduced Risk of
Osteoporosis
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NORA BMD and Fracture Rate
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Osteoporosis

• Mechanisms causing osteoporosis
• Imbalance between rate of resorption and
  formation
• Failure to complete 3 stages of remodeling
• Types of osteoporosis
• Type I
• Type II
• Secondary

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Osteoporosis - Types

• Postmenopausal osteoporosis (type I)
• Caused by lack of estrogen
• Causes PTH to overstimulate osteoclasts
• Excessive loss of trabecular bone
• Age-associated osteoporosis (type II)
• Bone loss due to increased bone turnover
• Malabsorption
• Mineral and vitamin deficiency

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Secondary osteoporosis
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Osteoporotic Vertebra
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Normal vs. Osteoporotic Bone
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When to Measure BMD in Postmenopausal Women

• All women 65 years and older
• Postmenopausal women lt65 years of age
• If result might influence decisions about
  intervention
• One or more risk factors
• History of fracture

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When Measurement of BMD Is Not Appropriate

• Healthy premenopausal women
• Healthy children and adolescents
• Women initiating ET/HT for menopausal symptom
  relief (other osteoporosis therapies should not
  be initiated without BMD measurement)

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Prediction of Fracture Risk

• All techniques (DXA, QCT, QUS) predict fracture
  risk

• American Association of Clinical Endocrinologists
• Endocrin Prac 2001 7 283-312

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Osteoporosis Can Be Assessed by DXA
DXA-assessed content is a proven effective method
for assessing osteoporosis related fracture
risk. Population surveys and research studies
demonstrate a decrease in bone density measured
by DXA predicts fracture at specific
sites. Marshall, D, et al Meta-analysis of how
well measures of bone mineral density predict
occurrence of osteoporotic fractures. British
Medical Journal. 3121254-1259, 1996.
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The McCue CUBA Ultrasonometry Technology That
Can Assess Osteoporosis
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Heel BUA is Significantly Lower in Subjects With
Future Hip Fracture.
Subjects who developed hip fracture showed
significantly (plt0.001) lower heel BUA results in
a two-year follow-up prospective study of 1,414
subjects. Porter, RW, et al Prediction of
hip fracture in elderly women a prospective
study. British Medical Journal. 301638-641,
1990.
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Discriminating Power of Heel BUA in Reflecting
Vertebral Osteoporosis
When assessing vertebral osteoporosis, there was
no statistically significant difference in the
discriminating power of Heel BUA or Spine, Femur
Neck or Trochanter BMD by DXA. Ohishi, T, et al
Ultrasound measurement using CUBA clinical
system can discriminate between women with and
without vertebral fracture. Journal of Clinical
Densitometry. 3227-231, 2000.
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Receiver Operator Characteristic Analysis of Hip
Fracture Risk
Schott, AM, et al Ultrasound discriminates
patients with hip fracture equally well as dual
energy x-ray absorptiometry and independently of
bone mineral density. Journal of Bone and
Mineral Research. 10243-249, 1995.
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Increasing Relative Fracture Risk is Seen with
Decreased BUA or BMD
Hans, D, et al Ultrasonographic heel
measurements to predict hip fracture in elderly
women the EPIDOS prospective study. Lancet.
348511-514, 1996. Bauer, DC, et al Broadband
ultrasound attenuation predicts fractures
strongly and independently of densitometry in
older women. Archives of Internal Medicine.
157629-634, 1997. Frost, ML, et al A
comparison of fracture discrimination using
calcaneal quantitative ultrasound and dual x-ray
absorptiometry in women with a history of
fracture at sites other than the spine and hip.
Calcified Tissue International. 71207-211,
2002.
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Increased Relative Fracture Risk is Seen With
Decreasing BUA
14,824 men and women were followed for an average
of 1.9 years to relate BUA to future fracture
risk. Subjects in the lowest 10th percentile of
BUA showed a relative risk of fracture 4.44 times
greater than those in the highest 30th percentile
of BUA. Khaw, KT, et al. Prediction of total
and hip fracture risk in men and women by
quantitative ultrasound of the calcaneus
EPIC-Norfolk prospective study. Lancet.
363197-202, 2004.
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Who Should Be Considered for Prevention or
Treatment?

• Postmenopausal women with T-score below 2.0 with
  no risk factors
• Postmenopausal women with T-score below 1.5 with
  one or more risk factors

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• Prevention of Bone Loss
• Calcium
• HRT
• SERMS
• Calcitonin
• Bisphosphonates

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