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Osteoporosis - Diagnosis and
Treatment
Dr. Sophia Ish-Shalom
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
S Ish-Shalom
Osteoporosis
• Important cause of mortality and
morbidity
• A disease that causes bones to lose
mass, weaken and fracture
• progression is slow, silent, painless
Rickets
Fish Oil
Bone Effects of Vitamin D Deficiency
• Ca X P insufficient insufficient mineralisation
• Osreoblasts continue bone deposition
• Endoosteal surface
• Periosteal surface
Rubbery matrix with
insufficient support
• Hydrates and expands under periosteal covering
 outward pressure on periosteal covering
innervated with sensory nerves
Vitamin D Metabolism
Food: Salmon, Mackerel
Cod liver oil, Yeasts, Plants,
Fortified Foods
Prostate, Placenta
Breast; Colon
Osteoblasts
Keratynocytes
Immune cells
1,25(OH)2D3
Regulation
of cell growth
(cancer
prevention)
Regulation
ofRegulation
immune
of immune
function
function
1/100 active
used to determine
vitamin D status
Dietary Reference Intake (DRI) of Vitamin D
• < 50 years – 200 IU/day
• > 51years - 400 – 600 IU/day
• In absence of sunlight for adults 600 – 1000 IU/day
• In Vitamin D deficiency state we absorb
• < 10 – 15% of dietary calcium
• < 60% of dietary phosphorus
• With adequate Vitamin D
• 30 % - 80% of dietary calcium
• 70 – 80 % of dietary phosphorus
Food
IU per serving
Percent
DRI
1,360
340
Salmon, cooked, 3½ ounces
360
90
Mackerel, cooked, 3½ ounces
345
90
Tuna fish, canned in oil, 3 ounces
200
50
Sardines, canned in oil, drained, 1¾ ounces
250
70
Milk, nonfat, reduced fat, and whole, vitamin D fortified, 1 cup
98
25
Margarine, fortified, 1 Tablespoon
60
15
Pudding, prepared from mix and made with vitamin D fortified
milk, ½ cup
50
10
Ready-to-eat cereals fortified with 10% of the DV for vitamin D, ¾
)cup to 1 cup servings (servings vary according to the brand
40
10
)Egg, 1 whole (vitamin D is found in egg yolk
20
6
Liver, beef, cooked, 3½ ounces
15
4
Cheese, Swiss, 1 ounce
12
4
Cod liver oil, 1 Tablespoon
Vitamin D Production
• Sun exposure in a bathing suit 1 minimal erythema
dose = ingestion of 20 000 IU
Use of sunscreen
100% in vitamin D
production
• Exposure of arms and legs 25% minimal erythema
dose (5 –15 min) 11 am – 2 pm x 3/w
25(OH)D3 Serum Level in Hip Fracture
Patients
94 (98 %) patients had inadequate 25(OH)D3 serum level
35
37%
36
37%
23
24%
2 (2%)
<
ng/ml
-
ng/ml
-
ng/ml
>
ng/ml
E Segal, S. Ish-Shalom, JAGS 2004
Osteoporosis
• Important cause of mortality and
morbidity
• A disease that causes bones to lose
mass, weaken and fracture
• 1:3 women and 1:8 men are affected
• progression is slow, silent, painless
‫מי סובל‪/‬ת מאוסטיאופורוזיס?‬
‫אישה אחת מכל ‪3‬‬
‫מעל גיל‬
‫‪...50‬‬
‫גבר אחד מכל ‪7‬‬
‫‪...60‬‬
‫מעל גיל‬
‫שברים אוסטאופורוטיים‬
‫שברים בחוליות‬
‫עמוד השדרה‪:‬‬
Only 33% of Osteoporotic Vertebral Fractures are
Clinically Diagnosed!
100 % Patients with vertebral fractures that
are visible on X-rays
50 %
Symptomatic (dorsalgia)
33 %
Clinically diagnosed
8%
Hospitalized
2%
Requiring long term care
2/3 of patients with vertebral fractures that are visible on X-rays are not diagnosed
Adapted from ROSS PD: Clinical Consequences of Vertebral Fractures: AM J Med 1997;103 (2A): 30S-43S
Grading Scheme for a Semiquantitative
Assessment of Vertebral Deformities after Genant
0 no deformity
1  20-25% vertebral height
 10-20% projected area
2  25- 40% vertebral height
 20%- 40% projected area
3  40% vertebral height
 40% projected area
‫שברים אוסטאופורוטיים‬
‫‪Colle’s Fracture‬‬
‫שברים אוסטאופורוטיים‬
‫שבר בצוואר הירך‪:‬‬
Bone remodelling
Quiescence
Lining cells
Activation
Resorption
Formation
Osteoclasts
Osteoblasts
Mineralization
Mineralized
bone
Quiescence
Bone structural
unit
Adapted from Compston 1996
1.8
BMD (g/cm2)
1.6
1.4
400
Mineral
density
1.2
1
0.8
0.6
+ 2SD
Fracture
threshold
0.4
0.2
Fractures
0
300
Mean
200
– 2SD
100
0
10
20
30
40
50
60
70
80
Fractures/10,000 patient years
Bone Mineral Density and Fractures
90
Age (years)
Birdwood 1996
Osteoporosis - Causes
•
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)
Osteoporosis - Causes
• Endocrine disease
– primary hyperparathryroidism
– thyrotoxicosis
– Cushing’s syndrome
Rheumatologic diseases
– rheumatoid arthritis
– ankylosing spondylitis
Osteoporosis - Causes
•
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)
Glucocorticoid Induced Osteoporosis
 GI Calcium Absorption
 PTH
 Urinary Calcium Excretion
 LH, FSH, Testosteron, Estrogen
Osteoprotegerin 
Bone Resorption 
Muscle Srength 
Bone Formation 
Oseoblast Apoptosis 
Growth Factors 
Traumarelated
factors
Fracture risk
Bone strength
Bone density
Geometry
Bone quality
•Microarchitecture
•Turnover
•Microdamage
•Mineralization
10 y probability of hip fracture in women by age
and femoral neck T-score
BMD- and age-associated risks are
gradient functions;
fractures occur in osteopenic
postmenopausal women
Kanis, Osteoporos Int 2001;12:989
Vertebral Fracture
Dual-energy X-ray Absorptiometry -
Case # 1: interpretation failure:
a “non-osteoporotic” 89 y old lady with a
fractured right femoral neck
Case # 2: a 27 y old women with
T-score -4.9 at L4; hardware failure
Case # 2: a 27 y old women with
T-score -4.9 at L4
Case # 2: hardware failure resolved
Definition of Osteoporosis in Women
According to WHO (diagnostic criteria)
Definition
Normal
Osteopenia
Osteoporosis
Bone
Strategy
T-Score > - 1 SD
Prevention
-1 SD > T-Score > - 2.5 SD
T-Score  - 2.5 SD
Treatment
Severe
Osteoporosis
Osteoporosis with fracture(s)
Kanis et al Osteoporos Int (1997)7:390-406
Management of Osteoporosis:
Pharmacological Therapy
• Calcium
• Vitamin D
• HT (not recommended for osteoporosis, but
•
•
•
•
if used for menopausal symptoms, efficient
for osteoporosis)
SERMs ( Raloxifen, EVISTA)
Bisphosphonates
Calcitonin
PTH analogues
Management of osteoporosis:
pharmacological therapy
• Calcium
• Vitamin D
• HRT
• SERMs
• Bisphosphonates
• Calcitonin
• PTH
Antiresorptive Drugs
• antiresorptive drugs (estrogen, SERMS,
bisphosphonates, calcitonin)  both the rates
of bone resorption (in weeks) and formation
(in months)
• bone mineral density is  by 3 - 8 % for the
first 2-3 years then plateaus; this reduces the
risk of fracture by 30 - 50% in various skeletal
sites
Therapeutic Agents in Osteoporosis
Decrease in Fracture Risk
Risedron Alendron
Raloxif
Calciton
Estrog
 in Fracture Risk
++
++
+
+
+
LS
+
++
NS
NS
+
Pr. Hip
in BMD
Risedron Alendron
++
++
+
++
++
‫הוכחה בשני‬
‫מחקרים או יותר‬
Raloxif
Calciton
+
+
Estrog
+
 BMD
LS
Pr. Hip
‫הוכחה במחקר‬
+
‫לא חד משמעי‬
+
‫ אין הוכחה‬NS
‫משמעותית‬
‫אין נתונים‬
ND
Ref.: Hochberg M et al. Drug & Aging 2000 Oct: 17(4) :317-330
Bisphosphonates: Pharmacology
• Bone-seeking
• Effective orally or IV
OH R1 OH
O = P—C —P = O
OH R2 OH
• Poor absorption orally
• Not metabolized, excreted
by the kidney
• Long skeletal retention
• Side chain determines
potency and side effects
Bisphosphonates: Mechanisms of Action
OH R1 OH
O = P—C —P = O
OH R2 OH
Reduce activity of
individual osteoclasts
• inhibit lysosomal enzymes
• inhibit lactate production
Reduce activation frequency
• inhibit recruitment of
osteoclast precursors
• inhibit differentiation of
osteoclast precursors
Increase osteoclast apoptosis
Bisphosphonates: Indications and Contraindications
Indications
• Prevention of bone loss in recently menopausal women
• Treatment of established osteoporosis
• May have benefits in many conditions characterized by
increased bone remodeling (eg, Paget’s disease,
hypercalcemia of malignancy)
Contraindications
• Active upper GI disease (some bisphosphonates cause
esophageal irritation)
• Hypocalcemia
• Renal insufficiency
Fracture Intervention Trial (FIT)
2,027 women with low femoral neck BMD
and one or more vertebral fracture
6
Placebo
5
5.0
Alendronate
4
Percent
of
patients
4.1
3
**
2
2.3
*
2.2
2.2
*
1
1.1
0
Clinically apparent
vertebral fractures
% reduction
55%
Hip
fractures
Wrist
fractures
51%
48%
**P< 0.001; *P< 0.05
Black DM et al, Lancet 1996;348:1535. © by The Lancet Ltd 1996. Reprinted with permission.
Estradiol and Raloxifene Occupy
the Same Ligand Binding Site
Kd= 86 pM
Kd= 54 pM
Adapted from Brzozowski AM et al., Nature 1997;389:753-58
Evista - Mode of Action of
Raloxifen
• Blocks the effect of estrogen in
the brain hot flaches
• Blocks the effect of estrogen in
the mammary gland breast
cancer
• Blocks the effect of estrogen in
the uterus  no vaginal bleeding
• Acts as estrogen in bone –
approved for the treatment of
osteoporosis
Bone Formation Drugs
Biosynthetic PTH
– stimulate bone formation
– overfill resorption cavities
– the increase in bone density continues
beyond two years
Effects of Treatments on
Lumbar-spine Bone Mineral Density
1.2
Bone Formation drug
1.1
Antiresorptive drug
1.0
Placebo
0.9
-1
0
1
2
Year
3
4
Antiresorptive versus Anabolic Treatment
Teriparatide Improves
Skeletal Architecture
Baseline
Patient treated
with teriparatide 20µg
Data from Jiang et al. JBMR 2003 (in press)
Follow up
Female, age 65
Duration of therapy: 637 days (approx 21 mos)
BMD Change:
Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%)
Total Hip:
+5.2% (group mean = 2.6 ± 4.9%)
Jiang UCSF
Therapeutic Management of Postmenopausal
Osteoporosis
Osteoporosis prevention
T-score >–2.5
Osteoporosis treatment
with or without
previous fracture
Osteoporosis treatment
with multiple fractures and at
risk for hip fracture
PTH
HRT
Bisphosphonates
Raloxifene
50
55
60
65
70
HRT=hormone replacement therapy
Age (years)
75
80
85
90
Comparison of BMD Changes During
Treatment with PTH 1-34 or Fosalan
Measurement Site
PTH
Fosalan
Lumbar spine
12.2±9.4*
5.6±5.0
Total hip
4.0±5.7*
2.5±3.2
Femoral neck
4.8±6.5*
1.7±4.3
Ultradistal radius
0.2±6.6
1.4±5.1
Paget Disease of Bone
Affected Sites