Osteoporosis

PATHOGENESIS
DIAGNOSIS
TREATMENT
Robert D. Auerbach, M.D. FACOG
Senior VP & Chief Medical Officer
CooperSurgical, Inc.

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

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

Bone cells

Osteocytes - derived
from osteoprogenitor
cells

Osteoblasts
Osteoclasts

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

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

Osteoclasts
Resorbe 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

Chemistry of the bone

Matrix
Mineral

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

Mineral
A calcium phosphate/carbonate
compound resembling the mineral
hydroxyapatite Ca10(PO4)6(OH)2
Hydroxyapatite crystals

Imperfect
Contain Mg, Na, K

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

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

Bone remodeling process

Coordination of Resorption and

Formation

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

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

Pathways of differentiation of
osteoclasts and osteoblasts

Hormonal Influence
Vitamin D
Parathyroid Hormone
Calcitonin
Estrogen
Androgen

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

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

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

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

Other systemic hormones

Estrogens

Increase bone remodeling

Androgens

Increase bone formation

Other systemic hormones

Growth hormone

Glucocorticoids

Increases bone remodeling

Inhibit bone formation

Thyroid hormones
Increase bone resorption
Increase bone formation

Local regulators of bone remodeling

Cytokines
IL-6
IL-1

Prostaglandins
Growth factors

IGF-I
TGF-

Osteoporosis
A disease characterized by:
low bone mass
microarchitectural deterioration of the bone
tissue

Leading to:
enhanced bone fragility
increase in fracture risk

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

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

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis

in Postmenopausal Women by Ethnicity

Pathogenesis of Estrogen
Deficiency and Bone Loss

Estrogen loss triggers increases in IL1, 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

Osteoclast Differentiation and

Activation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic

Differentiation and Activation

National Osteoporosis Risk Assessment (NORA):

Factors Associated With Increased Risk of
Osteoporosis

NORA: Factors Associated With Reduced

Risk of Osteoporosis

NORA: BMD and Fracture Rate

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

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

Secondary osteoporosis

Osteoporotic vertebra

Normal vs. osteoporotic bone

Risk Factors

When to Measure BMD in

Postmenopausal Women
All women 65 years and older
Postmenopausal women <65 years of
age:

If result might influence decisions about

intervention
One or more risk factors
History of fracture

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)

Prediction of Fracture Risk

All techniques (DXA, QCT, QUS)

predict fracture risk

American Association of Clinical Endocrinologists

Endocrin Prac 2001; 7: 283-312

Osteoporosis can be Assessed by DXA

Forearm
Hip

er
te
br
al
A
ll
Si
te
s

H
ip

Spine

re
ar
m

3
2.5
2
1.5
1
0.5
0
Fo

Relative Risk

Relative Risk of Fracture

per SD Decrease in BMD

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.
312:1254-1259, 1996.

The McCue CUBA: Ultrasonometry

Technology that can Assess Osteoporosis

BUA

110 Normal
dB/MHz

40
dB/MHz
Osteoporotic
Bone
Frequency

Heel BUA is Significantly Lower in

Subjects With Future Hip Fracture.
60

BUA (dB/sq MHz)

50
40
30
20
10
0
Fracture

No Fracture

Subjects who developed hip fracture showed significantly (p<0.001) 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. 301:638-641, 1990.

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. 3:227-231, 2000.
1

Area Under the Curve

0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Heel BUA

Spine BMD

Neck BMD

Trochanter BMD

Receiver Operator Characteristic Analysis

of Hip Fracture Risk
0.9

Area Under the Curve

0.85
0.8
0.75
0.7
0.65
0.6
0.55
0.5
Heel BUA

Fem ur Neck BMD

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. 10:243-249, 1995.

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. 348:511-514, 1996.
Bauer, DC, et al: Broadband ultrasound attenuation predicts fractures strongly
and independently of densitometry in older women. Archieves of Internal
Medicine. 157:629-634, 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.
71:207-211, 2002.
Relative Risk of Fracture

3
2.5
2
BUA

1.5

BMD

1
0.5
0
Hans, et al

Bauer, et al
Research Study

Frost, et al

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.

Relative Fracture Risk

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. 363:197-202, 2004.
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
<10

10 to <40

40 to <70

Percentile Category

70 to 100

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

NORA

NORA

Prevention of Bone Loss

Prevention of Bone Loss
Calcium
HRT
SERMS
Calcitonin
Bisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary