an excellent resource for bone chemistry

1. By.Dr.Karna Venkateswara reddy

2. • Introduction
• History
• Chemical Structure
• Types Of Bisphosphonates
• Pharmacokinetics
• Mechanism Of Action
• Drug Administration And Dosage
• Common Uses Of Bisphosphonates
• Contraindications Of Bisphosphonates

3. • Bisphosphonates (also called diphosphonates) are
a class of drugs that prevent the loss of bone
mass.
• Used in the treatment of many skeletal disorders-
Bone metastases,
osteoporosis,
Paget’s disease etc.

4. • The “bis” prefix is a term indicating two -
phosphonate groups, attached to a common
carbon atom.
• These are structurally similar to natural
pyrophosphate (PP), which is a normal product of
human metabolism that has a calcium chelating
property.

5. • These drugs have a high attraction for
hydroxyapatite crystals and thus rapidly
included into all parts of the skeleton.
• They are used as inhibitors of osteoclastic
activity to alleviate bone pain that results from
the release of biochemical mediators in
metastatic bone disease.

6. • In 1897, Von Baeyer and Hoffman reported the
synthesis of the first bisphosphonates.
• Initially used in chemical industry as
anticorrosive & anti-scaling agent by virtue of
their ability to inhibit formation of calcium on
surfaces.

7. • In 1960, Fleisch et al. first reported their
ability to inhibit hydroxyapetite dissolution in
bone.
• First human use of a bisphosphonate,
etidronate, was reported by Bassett et al. in
1969 for the treatment of Myositis Ossificans
Progressiva (MPO).
• Smith et al.(1971) were the first to report the
evidence of effectiveness of the
bisphosphonates for the treatment of Paget’s
disease of bone.

8. NON-NITROGENOUS
Olpadronate
NITROGENOUS
Tiludronate
Clodronate
Etidronate
Alendronate
Neridronate
Pamidronate
Risedronate
Ibandronate
Zoledronate

9. • Minimally modified side
chains (R1 R2) contain a
chlorophenyl group.
• Metabolized into a non-
hydrolyzable ATP analog
that accumulates within
osteoclasts and induces
apoptosis. which account
for its antiresorptive effect.
• Least potent.
Etidronate
Medronate
Clodronate
Tiludronate

10. • Contains nitrogen group (amino
terminal) in the side chain.
• Primarily inhibits bone resorption.
• Antiresorptive activity involves
inhibition of multiple steps in the
pathway from mevalonate to
cholesterol and isoprenoid lipids
that are required for the
prenylation of proteins that are
important for osteoclast function.
• They are 10-100 times more
potent than 1st generation BPs.
Alendronate
Pamidronate
Ibandronate

11. • Contain nitrogen atom
within a heterocyclic ring.
• These are upto 10,000
times more potent than 1st
generation.
Risedronate,
Zoledronate

12. • Inverse relation exists between pharmacologic activity and
oral bioavailability
• Absorption by passive diffusion from gut
• Milk and other dairy products, orange juice, coffee and
calcium and iron products reduce absorption
• Bound to plasma proteins
• 20-80% of the absorbed dose is rapidly taken up by bone.
• Remainder is rapidly excreted in urine
• Long skeletal retention (half life up to 10 years)

13. • Bisphosphonates are used to inhibit bone
resorption & they act through different mode
of actions:
1. Inhibit development of osteoclasts. Induction of
osteoclast apoptosis.
2. Reduction of osteoclast activity.
3. Prevention of development of osteoclasts from
hematopoietic precursors.
4. Stimulation of production of an osteoclast
inhibitory factor.

15. • There are 2 classes of BPs which have different
mechanisms of action:
• Non nitrogen containing BPs are taken up by the osteoclast and
cause cell apoptosis through activation of capsase pathway.
• Nitrogen containing BPs are not metabolised and affect protein
prenylation of osteoclast by inhibiting farnesyl diphosphate
(FPP) synthase, a key enzyme of the mevalonate pathway .

16. • The physicochemical effects are very similar to
pyrophosphate.
• Inhibit the formation and aggregation of calcium
phosphate crystals , even at very low
concentrations.
• Block the transformation of amorphous calcium
phosphate into Hydroxyapetite, and delay the
aggregation of apetite crystals.
• Bisphosphonates also delays the dissolution of
calcium phosphate crystals.

17. • All of these effects are related to the marked
affinity of BPs for the surface of calcium
phosphate where they bind onto the calcium
by chemisorption.
• BPs chiefly act as a crystal poison on both
growth and dissolution.

18. • The inhibition of bone resorption can be explained
largely by cellular mechanisms.
• Can be considered at three levels: tissue, cellular, and
molecular.
• The effect may be directly on the osteoclasts and may
be mediated, via other cells such as osteoblastic
lineage cells and macrophages.

20. Indications for Use
• Indications for bisphosphonates include such conditions
1. Postmenopausal
2. Glucocorticoid-induced osteoporosis,
3. Paget’s disease,
4. Osteolytic and osteoblastic bone metastases,
5. Fibrous dysplasia,
6. Heterotopic ossification,
7. Myositis ossificans.
8. Other bisphosphonates, medronate and oxidronate
are mixed with radioactive technetium and are
injected for imaging bone and detecting bone disease

21. Bisphosphonates in Metastatic disease
1. They control hypercalcemia,
2. Reduce bone pain,
3. Reduce the number of pathologic fractures,
4. Prolong survival.

22. • Intrvenous zolendronate and palmindronate
are the ones most useful and should be
combined with either chemotherapy or
hormonal therapy in women with metastatic
bone disease.
• Zolendronate is the first bisphosphonate
shown to be effective in both lytic and blastic
metastatic disease

23. • Studies suggest the use of bisphosphonates
As oral and local adjuvants in total joint
arthroplasties increase periimplant bone
density or reduce implant migration

24. Drug Interactions
• Bisphosphonates generally should not be taken with
antacids that contain aluminum or magnesium, bottled
water containing minerals, or calcium supplements
because these agents decrease bisphosphonate
absorption.
• A 2-hour interval between meals drug is recommended.
• Aminoglycosides taken with bisphosphonates may cause
severe hypocalcemia.

25. • Upset stomach
• Inflammation/erosions of esophagus
• Fever/flu-like symptoms
• Slight increased risk for electrolyte disturbance
• Uveitis
• Musculoskeletal joint pain
• Bisphosphonate related osteonecrosis of jaw
(BRONJ)

26. • Patients may be considered to have BONJ if
they have exposed bone in the maxillofacial
region for at least 8 weeks, are currently on or
have taken bisphosphonates and have no
history of radiotherapy to the jaws . (AAOMS )

27. Osteonecrosis of the right mandible after
tooth extraction in a patient taking
zoledronic acid for metastatic breast cancer.
Osteonecrosis of the palatal torus in a
patient with osteoporosis taking
alendronate.

28. Drug Administration And Dosage

29. Thank u…………