OSTEOPOROSIS

Prof.Dr.dr. R. Djokomoeljanto
FK UNDIP

De Laet CED & Pols HAP

(2000)

Osteoporosis is defined as a condition

characterized by low bone mass and microarchitectural deterioration of bone tissue,
with a consequent increase in bone fragility
and susceptibility to fractures.

Bone is An Active Organ Undergoing

Continuous Change:
1. to attain the targetted structure - modelling
2. to maintain the optimal structure - remodelling
3. to renew the old with new bone
4. to supply body calcium requirements.

Bone regeneration is mandatory

Modeling

Remodeling
reached

during development and growth, the

skeleton is sculpted to achieve its
shape and size by the removal of
bone from one site and deposition
at a different one.
once the skeleton has
maturity, regeneration continues in
the form of of periodic replacement
of old bone with new at the same
location.

Type of Bone
Cortical bone mechanical function, hard
collagen-mineralized, external parts of
long bones, 80 % ! 3 10 % remodelled
yearly.
Cancellous-trabecular-spongy 75 % of
total bone surface, metabolically active, 20
30 % remodelled yearly.

In adult skeleton the remodelling cycle

serves 2 functions:
1. to produce supply (acute or chronic) of
calcium to extracellular space
2. to provide elacticity and strength to the
skeleton

Pathophysyology of
Osteoporosis
a. Peak bone-mass

b. Bone formation.
c. Bone loss.
c.1. Age-related bone-loss
c.2. Postmenopausal bone-loss
c.3. Systemic diseases : hypogonadism,
hyperthyroidism, hyperparathyroidism,
neoplasia, strenuous exercise, DM, CRF
corticosteroid.

1. BMD reflects bone mass and state of

mineralisationi
2. The key of treatment is prevention
3. Osteoporosis can be optimally treated if
a. Bone microarchitecture is intact
b. Only slight bone loss
4. Begin with non drug management, be holistic.

Bone mineral density

Bone quality

Micro structure
Macro structure

- Hip axis length

- Femoral neck width
- Vertebral body size

- Thickness
- Porosity
- Connectivity
- Anisotropy
- Inhomogenity

Bone strength

Material properties
- Mineralization
- Collagen structure
- Ultrastructure

Extraskeletal factors
- Propensity for falling
- Bone marrow status

Fracture risk
Determinants of fracture risk, In addition to be bone mineral density, a number
of others factors, both skeletal and extraskeletal, affect fracture risk. The
individual factors listed represent examples.
(Gluer, BcEM, 2000)

Pathogenesis of osteoporotic fracture

Menopause

Genetic
factors

Others factors

Increased bone loss

Genetic
factors

Hormonal
factors

Mechanical
factors

Nutritional
factors

Inadequate peak bone mass

Osteopenia (i.e. low bone density)

Osteoporotic fracture

Trauma

Falls

E
R
U
T
C
A
FR

Bone
strength
Padding

Postural
reflexes

Architecture
and
geometry

Bone mass

Bone material
strength

Hormones

Nutrition
Exercise
Lifestyle

Interplay of the major groups of pathogenetic factors leading

to osteoporotic fractures.
(Copyright Robert P. Heaney, Omaha, NE. 1995. Reproduced with permission)
(Heany, EMCNA, 1998)

Appendicular
Fractures caused by minimal trauma

Proximal femur
(intertrochanteric or
intracapsular)

Proximal
humerus

Most common types

Distal
radius

Pathophysyology of
Osteoporosis
a. Peak bone-mass

b. Bone formation.
c. Bone loss.
c.1. Age-related bone-loss
c.2. Postmenopausal bone-loss
c.3. Systemic diseases : hypogonadism,
hyperthyroidism, hyperparathyroidism,
neoplasia, strenuous exercise, DM, CRF
corticosteroid.

The characteristics of OP type I

and OP type II
Characteristics

Female / male ratio

Range of age
The affected bone
Fracture predisposition
Type of bone loss
Parathyroid function
Main patophysiology
Main factor
Calcium need in the diet

Type I
(postmenopausal)
6:1
51 65
trabec > cortic
spinal, radius
fast, accelerated
decrease
resorption >
estrogen loss
low

Type II
(senile)
2:1
75
trab=cort
hip
gradual
increase
formation <
ageing
important

Risk factors for postmenopausal

osteoporosis (OP-1)
Women
Postmenopausal
Pale white skin
Premature menopause (surg?)
Positive family history
Nullipara
Gastrectomy, small stature

Corticosteroid treatment
Anticonvulsant treatment
Hyperparathyroidism
Thyrotoxicosis
Smoking
Alcohol abuse
Inactivity

Increasing age bears consequence of increased

fracture.
Rates in men are lower and at a later age than in
women.

Menopause and bone mineral density

The constituents of bone

Bone
Extracellular matrix
(connective tissue)
Collagen fibris
(type 1)

Non-collagenous bone
proteins
-Osteocalcin
-Osteopontin
-Bone sialoproteins
-Thrombospondin
-Fibronectin
-Phosphoproteins
-Osteonectin
-Proteoglycans
-Matrix GLA protein

Cells

Ground
substance

Osteoblasts

Osteoclasts

Glycosaminoglycans
Mineral
(mainly calcium hydroxyapatite)

Osteocytes

Weight bearing exercise increase the BMD

in postmenopausal women

Normal and osteoporotic bone

Basic Multicellular Unit (BMU)

OB differentiate from MPs, produce factors (CSF-1 for M

dev and RANK-L potent OC diff signal), connected by
gap-junctions, secretes matrix (OC,coll-1, ALP-min)

Osteoclast bone resorption.

Attached via integrin-mediated binding to matrix protein.
Acid and enzymes are secreted into the extracellular
lysosome.

(A)

Activation of resting OB on the surface of bone and stromal marrow.

Release of cytokines, m-CSF,TGF-, TNF enhance recruitment of MNgiant cells to become bone-resorbing cells (OC). Inhibited by OPG.

(B)

OPG being to act as a dummy receptor for the OPG ligand (=OPGL,
RANKL). OPGL bind RANK-rec.activator initiate OC activation and
subsequent bone resorbtion.

(C)

OB lay down collagens, regulate mineralization, with mesenchymal

cells (involving Cbfal, a transcription factor, differentiate to bone.
During resorption IGFs/GFs released to recruite new OB to surface.

Collagen degradation by OC produces markers of bone

ressorption while OB activities producing bone formation
markers.

Examinations
1.Anamnesis and physical examinations
2.Bone mass and mineral density examination
3.Ideally BMD (S-DPA, DEXA, Q-CT)
4.Laboratory indicators for formation
(osteocalcin, bone specific alfo, PICP) and
resorbtion (hydroxyproline, DPYD,PYD or
NTX)

The use of BMD and biochemical

marker of bone remodelling:
a. BMD assess the risk of fracture (S-DPA, DEXA, Q-CT)
Estimate the bone mass , mineral and its density
WHO score : women, proximal femur, DEXA ( -2.5> SD treat!
30% of whom become osteoporotic.
b. Markers assess the ongoing process resorption or formation
Resorption markers: HyPro, Pyridinoline and Deoxy-P (PYD)
collagen cross-linked N-telopeptide (NTX)
Formation markers: osteocalcin, BSAP, PIPC

Diagnostic Criteria for Osteoporosis

- 1.5 SD

- 2.5 SD

Osteoporosis

Osteopenia

Normal (young)

Effective Drugs Available for:

Bone formation:
Sodium fluoride
Anabolic steroid
Anti resorption :
Bisphosphonate
Estrogen
Calcitriol
Calcitonin

Pharmacologic Monotherapy for

Established Osteoporosis
Item

Effect

Estrogen
Bisphosphonates
Calcitonin
Calcium
Calcitriol (vit D3)
Anabolic steroids
Sodium fluoride
Parathormon

Antiresorbtive
Antiresorbtive
Antiresorbtive
Antiresorbtive / formative
Antiresorbtive / formative
Antiresorbtive / formative
Bone formation stimulus
Bone formation stimulus

(hPTH 1-34/1-38)
Gambert et al. 1995

Drugs for The Prevention of Spine

and Hip Fractures
Spine fractures

Hip fractures

Evidence based
Alendronate
Raloxifene
Risendronate
Almost evidence based
HRT
Unacceptable evidence
Etidronate, calcitonin,
Calcium, vit D analogues
Fluoride, anabolic steroids
E Seeman, B-EM 2000

Alendronate
Risedronate

HRT

Generation of Biophosphonates
Chemical Modification

Examples

Antiresorptive Potency

First-generation
Short alkyl or halide side chain

Etiddronate

Tiludronate*
Pamidronate
Alendronate

10
100
100 - 1000

Risedronate
Ibandronate
Zoledronate

1000 - 10,000
1000 10,000
10,000 +

Second-generation
Amino-terminal group
Third-generation
Cyclic side chain

*Tiludronate has a cyclic side chain, not an amino-terminal group, but is generally
classified as a second-generation compound based on its time of development and
potency (Watts, CEM, 1988).

Corticosteroids
Gastointestinal
Calcium absorption
Urinary calcium
excretion

Calcium

PTH ?

Osteoblast
bone formation

Muscle
mass

Effects on:
GH, IGF-1, TGF-

Sex hormone effects:

Adrenal androgens
Estrogen
Testosterone

Osteoclast
bone resorption

Osteoporosis

Corticosteroids induce bone loss through several mechanisms

(Lane & Lukert, CEM, 1998)