Bone Remodeling Cycle in Normal Bone

Osteoclasts
digest bone within a
sealed resorption vacuole

Resorption
Bone

Reversal

Resting
Bone

Apoptotic
osteoclasts

Lining
cells

Mature osteoblasts
building osteoid
tissue
Mineralization

Bone
Preosteoblasts

Bone

Formation

Illustration Copyright 2009 Nucleus Medical Art, All rights reserved. www.nucleusinc.com

Role of the osteoclast in bone pathology

Tumour cells
Primary Bone secondaries
Systemic factors
Local factors
Osteoclast activity
Osteolysis Direct bone destruction
Growth
factors
Activated
osteoclast
Bone
Bony complications

Why Bone Remodeling?

Allows skeleton to
Respond to mechanical loading
Repair and prevent microdamage (wear
& tear)
Maintains quality control

Release growth factors and minerals

(calcium and phosphate) stored in matrix
into circulation
All bone cells participate in remodeling
Considerable energy expended to remodel the
skeleton

Osteoclast Structure and

Function
Function bone resorption

Highly specialized cytoskeletal structures

Ruffled border
Sealing zone
Attach to and dissolve bone matrix

Produce tartrate-resistant acid phosphatase

(TRAP), lysosomal enzymes, cathepsin K,
and integrins
Express calcitonin receptors and RANK
Major therapeutic target in osteoporosis

Consequences of Increased
Bone Resorption

Increased
bone
resorption

Hypercalcaemia

Fracture

Bone

Bone pain

Antiosteoclast/Antiresorptive Agents
Estrogen

Mechanism of Fracture Risk

Reduction
Antiresorptive therapy
Reduce bone turnover
Stabilize or
improve
microarchitecture

Increase BMD

Decrease in fracture
risk

Bisphosphonates

These analogs of pyrophosphate, including

etidronate, risedronate, alendronate,
ibandronate ,and zoledronic acid used for the
treatment of disorders of bone remodeling,
such as
osteoporosis drug of choice
Paget's disease,
bone metastases and
hypercalcemia of malignancy
Decrease vertebral, hip, and nonvertebral
fractures

bisphosphonates
The

Bisphosphonate
Pharmacology
Proposed mode of action
Aminobisphosphonates

Bisphosphonates

Mature
osteoclasts Prostaglandins
Precursor
and other
cells
factors
Accession

Tumour
cells

Bisphosphonates
PA-12

Zoledronic Acid
Zoledronic acid is a new, highly
potent bisphosphonate
Heterocyclic nitrogen-containing
bisphosphonate composed of
A core bisphosphonate moiety
An imidazole-ring side chain
containing 2 critically
positioned nitrogen atoms

PA-13

Caution
Oral bisphosphonates may induce GI intolerability
A physician may not want to give an oral
bisphosphonate to patients with GI diseases
(achalasia, scleroderma, Barretts, etc)
In clinical practice, bisphosphonate blood levels
cannot be measured, creating uncertainties
around bone bioavailability in certain clinical
management scenarios
IV delivery requires patient adherence

Adverse effects:
These include diarrhea, abdominal pain, and
musculoskeletal pain. Alendronate, risedronate,
and ibandronate are associated with esophagitis
and esophageal ulcers.
To minimize the risk of esophageal irritation,
patients should remain upright for at least 30
minutes (60 minutes for ibandronate) after taking
a bisphosphonate.
Osteonecrosis of the jaw has been reported
with bisphosphonates. Etidronate is the only
member of the class that causes osteomalacia
following long-term, continuous administration.

Available Bisphosphonates for

Osteoporosis
Oral
Etidronate (not US)
Chlordronate (not US)
Alendronate (daily, weekly)
Risedronate (daily, weekly, monthly)
Ibandronate (daily, monthly)
Intravenous
Ibandronate (quarterly)
Zoledronic acid (annual)
Off-label
Pamidronate (IV quarterly)

Selective estrogen-receptor
modulators
Estrogen-progestogen therapy is no longer
the therapy of choice for the treatment of
osteoporosis in postmenopausal women
because of increased risk of breast
cancer, stroke, venous
thromboembolism, and coronary
disease
Raloxifene a selective estrogen-receptor
modulator approved for the prevention
and treatment of osteoporosis.

Raloxifene

Calcitonin
Derived from

 adverse effects of the intranasal

formulation include rhinitis and other
nasal symptoms.
parenteral formulation of calcitonin is
available for intramuscular or
subcutaneous injection, but it is
infrequently used in the treatment of
osteoporosis.

Teriparatide
Teriparatide

Algorithm for the management of osteoporosis in

postmenopausal women

Algorithm for the management of osteoporosis in

men

Conclusions
Antiresorptive

Conclusions
Both oral as well as intravenous

Ultimate Goal
To minimize fracture risk by achieving
normal bone strength with therapy
that is safe, well-tolerated, easy to
administer, and inexpensive

New and Emerging

Treatments
Antiresorptive (anticatabolic)
Denosumab
Odanacatib
Lasofoxifene
Bazedoxifene
CE/bazedoxifene
New delivery systems
oral salmon
calcitonin

Osteo-anabolic

(bone-

forming)

Sclerostin inhibitor
Variations of PTH
Endogenous PTH
stimulation calcium
sensing receptor
antagonist (calcilytic)
New delivery systems
transdermal PTH

Strontium ranelate
Combinations of antiresorptive and

Pencegahan Risk Factors