ANTIOSTEOCLAST

Bone Remodeling Cycle in Normal Bone

Osteoclasts
Resorption digest bone within a
sealed resorption vacuole

Bone

Resting Reversal

Apoptotic
Bone osteoclasts Bone

Preosteoblasts

Mature osteoblasts
Bone
building osteoid tissue
Mineralization 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

Growth Osteolysis Direct bone destruction

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

Hypercalcaemia
Increased
bone
resorption
Fracture

Bone Bone pain

Antiosteoclast/Antiresorptive Agents
Estrogen

Calcitonin

Bisphosphonates

SERMs (selective estrogen receptor modulators)

Anti-RANK ligand antibody (in development)

Cathepsin K inhibitors (in development)

 Mechanism of Fracture Risk Reduction

Antiresorptive therapy

Reduce bone turnover

Stabilize or improve
Increase BMD
microarchitecture

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 bisphosphonates inhibit osteoclastic bone

resorption via a mechanism that differs from that
of other antiresorptive agents

Bisphosphonates attach to hydroxyapatite binding

sites on bony surfaces, especially surfaces
undergoing active resorption.

When osteoclasts begin to resorb bone that is impregnated

with bisphosphonate, the bisphosphonate released during
resorption impairs the ability of the osteoclasts to form the
ruffled border, to adhere to the bony surface, and to produce
the protons necessary for continued bone resorption
Bisphosphonates also reduce osteoclast activity by
decreasing osteoclast progenitor development and
recruitment and by promoting osteoclast apoptosis

Treatment with bisphosphonates decreases the risk of

bone fracture in patients with osteoporosis.
Bisphosphonates are preferred agents for the prevention
and treatment of postmenopausal osteoporosis
C

Bisphosphonate Pharmacology
Proposed mode of action
Aminobisphosphonates Bisphosphonates

Mature
Precursor osteoclasts Prostaglandins
cells and other
factors
Accession

Tumour
cells

Bisphosphonates

PA-12
C

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, Barrett’s,
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 is a first-line alternative for
postmenopausal osteoporosis in women who
are intolerant to bisphosphonates.

It increases bone density without increasing the

risk of endometrial cancer. In addition, raloxifene
may reduce the risk of invasive breast cancer
 adverse effects

risk of venous thromboembolism

hot flashes and

leg cramps
 Calcitonin
Derived from parafollicular cells of the thyroid gland

Inhibits bone resorption

Available in nasal, subcutaneous, and oral formulations

Nasal formulation demonstrates reduction in vertebral fracture only in the 200

IU/spray formulation; lower and higher doses had no effect; nor has any dose
available shown nonvertebral fracture risk reduction

Has excellent safety profile; ability to reduce pain with

formulations other than injectable uncertain
• 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 is a recombinant segment of human parathyroid
hormone

administered subcutaneously →osteoporosis

Teriparatide is the first approved treatment for osteoporosis that

stimulates bone formation.

Other drugs approved for this indication inhibit bone resorption.

It is also effective in the treatment of glucocorticoid-induced

osteoporosis.
Algorithm for the management of osteoporosis in postmenopausal women
Algorithm for the management of osteoporosis in men
 Conclusions
Antiresorptive and anabolic therapies are both available to
manage postmenopausal osteoporosis

Antiresorptives: calcitonin, selective estrogen receptor

modulators, and bisphosphonates, all have unique mechanisms
to reduce fracture risk

Bisphosphonates can reduce the risk for vertebral, nonvertebral,

and hip fractures and although individual clinical trials show
differences in efficacy, the lack of head-to-head fracture trials
precludes validation of any superiority of 1 bisphosphonate over
another
 Conclusions

Both oral as well as intravenous bisphosphonates are

available. Intravenous allows delivery without GI side
effects, and assures drug delivery to bone in circumstances
where absorption of oral bisphosphonates is uncertain

Teriparatide stimulates bone formation and is especially

useful in patients at high risk for fractures or who do not
“respond” to alternative osteoporosis pharmacologic agents
 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) Osteo-anabolic (bone-forming)
• Denosumab • Sclerostin inhibitor
• Odanacatib
• Variations of PTH
• Lasofoxifene
• Endogenous PTH stimulation –
• Bazedoxifene
calcium sensing receptor
• CE/bazedoxifene antagonist (calcilytic)
• New delivery systems – oral
• New delivery systems –
salmon calcitonin
transdermal PTH

Strontium ranelate
Combinations of antiresorptive and anabolic
Pencegahan Risk Factors
 Dia-lah yang menciptakan kamu dari tanah kemudian dari setetes
mani, sesudah itu dari segumpal darah, kemudian dilahirkannya
kamu sebagai seorang anak, kemudian (kamu dibiarkan hidup)
supaya kamu sampai kepada masa (dewasa), kemudian (dibiarkan
kamu hidup lagi) sampai tua, di antara kamu ada yang diwafatkan
sebelum itu. (Kami perbuat demikian) supaya kamu sampai kepada
ajal yang ditentukan dan supaya kamu memahami(nya).
(QS.Al Mu’min :67)