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Post menopausal

osteoporosis

Submitted by:-
Amit Kochhar
B.O.T. 2nd year
Pt. D.D.U. I.P.H.
Osteoporosis

PATHOGENESIS
DIAGNOSIS
TREATMENT
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

 Calcificationoccurs 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
 Signalfrom 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
 Increases bone remodeling
 Glucocorticoids
 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-β
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 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
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 over stimulate 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
 Allwomen 65 years and older
 Postmenopausal women <65 years of
age:
 Ifresult 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
 Alltechniques (DXA, QCT, QUS)
predict fracture risk
Osteoporosis can be Assessed by DXA

DXA-assessed content is a
Relative Risk of Fracture proven effective method for
per SD Decrease in BMD assessing osteoporosis related
fracture risk.
3 Population surveys and research
2.5 studies demonstrate a decrease
Relative Risk

in bone density measured by DXA


2
Forearm predicts fracture at specific sites.
1.5 Hip
1 Spine
Marshall, D, et al: Meta-analysis
0.5 of how well measures of bone
0 mineral density predict occurrence
of osteoporotic fractures. British
m

al
ip

s
ite
ar

br
H

Medical Journal. 312:1254-1259,


S
re

te

ll
er
Fo

A
V

1996.
The McCue CUBA: Ultrasonometry
Technology that can Assess Osteoporosis

110 Normal
BUA dB/MHz

40
dB/MHz
Osteoporotic
Bone
Frequency
Heel BUA is Significantly Lower in
Subjects With Future Hip Fracture.

60

50

BUA (dB/sq MHz) 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
0.9
0.8
Area Under the Curve

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
0.85
Area Under the Curve 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.
3

2.5
Relative Risk of Fracture

2
BUA
1.5
BMD
1

0.5

0
Hans, et al Bauer, et al Frost, et al
Research Study
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. 363:197-202, 2004.

5
4.5
4
Relative Fracture Risk

3.5
3
2.5
2
1.5
1
0.5
0
<10 10 to <40 40 to <70 70 to 100
Percentile Category
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