This document provides an overview of bisphosphonates including their history, chemical structure, types, mechanism of action, uses, administration, and potential side effects like BRONJ. Some key points: - Bisphosphonates are a class of drugs that prevent bone loss and are used to treat bone metastases, osteoporosis, and Paget's disease. - They have a high affinity for hydroxyapatite crystals in bone and inhibit osteoclast activity and bone resorption. - Nitrogen-containing bisphosphonates are more potent than early non-nitrogenous versions. Mechanisms of action differ between the two classes. - While bisphosphonates showed

1. PRESENTED BY:
DR. YOGENDER SINGH
PG II

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

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.
(Walia MS, Arora S, Singal B. Jaw Osteonecrosis a Risk Factor in Bisphosphonate Therapy - A Dental Concern. J Oral Health
Comm Dent 2010; 4: 72-7.)

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.
Rodan GA. Mechanisms of action of bisphosphonates. AnnuRev Pharmacol Toxicol 1998; 38:
375-88.

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.
(Shinozaki T, Pritzker KP. Regulation of alkaline phosphatase: Implications for calcium pyrophosphate dehydrate crystal
dissolution and other alkaline phosphatase functions. J Rheumatol 1996; 23:677-83.)
(Armitage GC, Lundgren T. Risk Assessment of the Implant Patient. Clin Periodontol Implant Dent 2008; 5: 634-51.)

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 (Didronel)
Alendronate (Fosamax)
Neridronate
Pamidronate
Risedronate (Actonel)
Ibandronate (Boniva)
Zoledronate (Zometa,
Aclasta)

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 (Form insoluble complexes)
• 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. (Hughes DE et al.1995)
2. Induction of osteoclast apoptosis. (Sato M et al. 1990)
3. Reduction of osteoclast activity. (Hughes DE et al.1989)
4. Prevention of development of osteoclasts from
hematopoietic precursors. (Vitte C et al. 1996)
5. Stimulation of production of an osteoclast
inhibitory factor. (Coluccis S et al. 1998)

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. (Benford HL et al. 2001)
• 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 .
(Luckman SP et al. 1998)

17. • 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.
(Fleisch H, Russell RGG, Bisaz S, Mu¨ hlbauer RC, Williams DA 1970 The inhibitory effect of phosphonates on the formation of
calcium phosphate crystals in vitro and on aortic and kidney calcification in vivo. Eur J Clin Invest 1:12–18)

18. • 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.

19. • 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. • At this level, the action of the active
bisphosphonates appears to be the same for all, i.e.,
a reduction in bone turnover.
• This is shown by a decrease in both bone resorption
and bone formation, as assessed in humans by
calcium-45 kinetics, biochemical markers and
morphology.

21. • Under normal conditions, destroyed bone is
replaced by bone formation.
• In adults this occurs mostly at the trabeculae and
the cortex.
• The morphological dynamic unit of the turnover
is the BMU.
• The remodeling process in this unit starts with
the erosion of a certain amount of bone through
osteoclasts on the surface of the trabeculae, as
well as on the surface or the interior of the
cortex.

22. • The resorption follows a linear path, forming a canal
within the cortex and a trench on the surface.
• The destruction is followed by a refilling of the
excavation by the osteoblasts.
• The final morphological entity is called the bone
structural unit (BSU).
• It corresponds to an osteon within the cortex and has
been termed a hemiosteon when it is at the surface
of the bone.

23. • The total bone resorption and formation will therefore
depend upon the number of BMUs present at any time
which, in turn, will depend upon both the number of
BMUs formed and the length of time they are active.
• Under normal conditions, the amount of bone formed in
each BMU equals the amount destroyed, so that the
balance is zero.
• In osteoporosis, however, a greater amount of bone is
resorbed than formed, leading to a negative balance.

24. • The bisphosphonates act at the individual
BMU level by decreasing the depth of the
resorption site .
• Since the amount of new bone formed in the
BMU is not decreased, but possibly even
increased .
• The local and consequently the whole body
bone balance will be less negative or might
even be positive.

25. • The effect both on the general turnover and
the local balance will lead to:
Less trabecular thinning.
A decreased number of trabecular
perforations
A smaller erosion of the cortex.
Thus slowing down the decrease in bone
strength and the occurrence of fractures.

26. • Reasons to accept that bisphosphonates can lead to a
positive calcium and bone balance, both in animals and in
humans.
1. One is inherent to bone turnover.
 A decrease in bone resorption is not immediately followed
by the diminution of formation, so that a temporary
increase in balance through a reduction in the remodeling.
2. After the decrease in turnover, the new BSU formed will be
remodeled later than it would be normally. It therefore has
more time to finish the lengthy process of mineralization.
 This will lead to a higher calcium content and, therefore, a
higher bone mineral density and content.

27. 3. If the decrease in resorption depth at individual
remodeling sites is not matched by a decrease in
formation in the individual BMU, the local bone
balance in the BMU will be positive.
4. The last possibility is an increase in the amount
bone formed at the level of the BMU.

29. • At this level the final target of bisphosphonate
action is the osteoclast.
• Four mechanisms appear to be involved:
1) Inhibition of osteoclast recruitment;
2) Inhibition of osteoclastic adhesion;
3) Shortening of the life span of osteoclasts;
4) Inhibition of osteoclast activity.

30. • The first three mechanisms will lead to a decrease in
the number of osteoclasts. (observed in humans)
• All four effects could be due either to a direct action
on the osteoclast or its precursors.

32. Hwang and Wang, 2007

36. • 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)

37. • 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 )

38. 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.

39. Generalized osseous sclerosis of uniform thickness involving the
cortical plates and the lamina dura.

40. BP reduces vascularity of bone due to their anti
angiogenic properties.
 Suppression of bone turnover
 Soft tissue toxicity
 Compounding effects such as:
• presence of infection
• medications
• pathologies
may suppress bone or soft tissue healing.

42. • BPs accumulate in high turnover areas like mandible
than elsewhere.
• As a result of trauma or infection bone cannot
respond adequately.
 Masticatory Forces
– Chronic Low Grade Trauma
– Unable to repair micro-fractures
 Necrotic Bone
 Bony sequestrum

43. • For patients about to start a course of i.v. BPs,
the goal of treatment is to minimize the risk of
developing BONJ.
• If systemic conditions permit, initiation of i.v.
BPs is delayed until dental health is optimized,
i.e. 14-21 days for extraction site to
mucosalized.
• Examine prostheses for sharp edges.

46. • If there is exposed bone but no signs of
infection (AAOMS Stage 1) the treatment is
CHX rinses and analgesics.
• Where there is exposed bone and localized
infection (AAOMS Stage 2) . Antibiotics are
prescribed.

48. • The goal of surgical treatment is the removal of
necrotic bone and to create soft tissue coverage
over healthy bone.
• Most commonly symptomatic bony sequestrum
are removed with minimal soft tissue
disturbance.
• If there are large segments of necrotic bone more
radical surgical approaches are advocated.

50. • It is suggested that cessation of the BPs allows
regeneration of osteoclasts and some improvement in
bone turnover.
• For a patient who has been taking an oral BP longer
than 3years, it should be discontinued, 3 months
before and 3 months after the surgical procedure, if
approved by the patient’s physician.
• Serum C-telopeptide (CTx) levels should be greater
than 150 pg/mL before any surgical procedure, and
rechecked at the time of surgery.
(Lam DK, Sandor GKB 2007)

51. • BRONJ patients have fewer teeth, greater CAL, and
less alveolar bone support compared with controls
after adjusting for number of BP infusions.
(Vivek Thumbigere-Math,* Bryan S. Michalowicz,* James S. Hodges,† Michaela L. Tsai, Karen K. Swenson,‡
Laura Rockwell,‡ and Rajaram Gopalakrishnan§J Periodontol2014;85:226-233.)

52. • In early 1990’s an increased application of
BPs as host modulating agents was seen for
the treatment of periodontal disease.
• Many animal studies proved their high clinical
efficacy in inhibiting the progression of
experimentally induced periodontitis.
• These improvements, especially alveolar bone
gain, were also achieved in many human
clinical trials.

54. • In spite of these improvements in periodontal status
shown by BPs, they could never reach the stage of
general periodontal use as host modulating agents
due to their adverse effects.

55. • YAFFE A et al. (2003) found that in local drug
delivery of tetracycline in combination with
alendronate showed significant reduction in
alveolar bone loss.
• A R PRADEEP et al. (2012) in two different studies
found significant reduction in PD and CAL and
also more percentage of bone fill after using 1 %
of Alendronate gel in the treatment of both
chronic as well as aggressive periodontitis.

56. •As these human studies indicate, local drug delivery
of BPs show a ray of hope to be used as local host
modulating agents in periodontal therapy.
•This mode of application can overcome the adverse
effects associated with systemic administration of BPs,
while at the same time retaining the property of bone
sparing.

57. • In experimentally induced periodontitis in monkeys showed
that Alendronate when given I/v biweekly at a dose of
0.05mg/kg could retard bone loss around affected teeth
when compared with controls but had no effect over pocket
depth . ( Burnsvold LA et al. 1992)
• Another study shows a dose of 0.05mg/kg of alendronate
could inhibit bone loss but no effect is seen at higher
dosages(0.25mg/Kg). Which coincides with the finding that
alendronate is released in acidic environment (inflamed
periodontal pocket) from hydroxyapetite and has locally
cytotoxic effects to other stromal cells. (Sato M et al. 1991)

58. • Finding indicate that alendronate is a valuable
therapeutic medicine which can be used for the
treatment of periodontal disease either alone or
in combination with regenerative components
like anti-inflammatory drug, bone graft, material
and guided tissue regeneration or even with
dental implants. (Kaynak D et al. 2003)
• Lane et al. 2005 suggested that BPs treatment
improves the clinical outcome of non-surgical
periodontal therapy and may be an appropriate
adjunctive treatment to severe periodontal bone
loss.

59. • A newely developed BPs, TRK-530 (disodium
dihydrogen [4-(methylthio) phenylthio]
methanebisphosphonate), has recently been
shown to have anti-inflammatory, anti-bone
resorbing activity as well as dose dependent
local anticalculogenic action.
(Sikder MNH et al. 2004)

60. • Topically administered BPs reduces the root
resorption associated with orthodontic tooth
movement and alveolar bone resorption
following periodontal surgery.
(Igarashi K 1996) (Yaffe A 2000)
• BPs also reported to modulate cementoblast
behavior through the regulation of gene
expression, and thus has the potential for
cementum formation and mineralization
modifiers. (Chun Y-HP, Foster BL 2005)

61. • Alendronate found to inhibit bone resorption,
induced or as result of flap elevation &
RAP(The phenomenon is a transient burst of
localized remodeling process following
surgical wounding of cortical bone).
(Yaffe A et al. 1994)

62. • In nuclear medicine when combined with
radio-labeled BPs, can be used to detect
periodontal bone loss.
(Kaplan ML et al. 1978), (Jeffcoat ML et al. 1982, 1985), (Nicolay OF et al. 1986)

63. • Studies shows the potential of topical BPs application to
enhance osseointegration of dental implants.
(Borromeo GL et al. 2011)
• Its application on dental implants, with or without
calcium phosphate layer promoted implant-bone contact
and increased the amount of bone peripheral to implants
in dogs. (Jeffcoat MK. 2006)
• Zuffetti et al.2009 reported that bisphosphonate-treated
implant showed more contact with newly formed bone
than the control implant.

64. • However, despite of these potential benefits, it may
contribute the development of BON.
• Implant patient who has been taking an oral BPs for
osteoporosis is the possible risk of developing
osteonecrosis of jaw after implant placement.
• Oral BPs have been reported to be associated with
implant failure.
• Cheng et al. 2009 reported this risk to be 0.88% of the
patients receiving oral BPs.
• It is likely that the length of time a patient has been
taking oral bisphosphonates is important in
determining the level of risk.

65. • Since oral bisphosphonates slowly accumulate in
bone with time, an osteoporosis patient who has
been taking the drug for one year is at a lower
risk of developing osteonecrosis of jaw or implant
failure than someone who has been on the drug
for many years.
• In general, it is not recommended that implants
be placed in patients who have been on the drug
for more than 3 years.
• Prolonged use of bisphosphonates is a
contraindication to implant placement.
(Starck WJ, Epker BN 1985)

66. • Implants- “Currently not contra-indicated if
taking bisphosphonates but prudent to gain
informed consent which should be
documented (risk assessment)”

67. • Physicians and dentists should be fully updated
regarding the potential complications in the
management of patients on BPs.
• Effective communication process between prescribing
physicians, dentists and patients on BPs, is needed.
• BON is much lower in patients receiving oral BPs as
compared with patients receiving intravenous BP
therapy and good oral hygiene, accompanied by
regular dental care using non-invasive procedures, is
the best way to minimize this risk, if it exists.

68. •Herbert Fleisch. Bisphosphonates: Mechanisms of Action. Endocrine Reviews 19(1): 80–100.
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in the treatment of bone diseases. Musculoskelet Neuronal Interact 2007; 7(1):2-8.
•Angelo Mariotti. Bisphosphonates and Osteonecrosis of the Jaws.
•Carol Tekavec, CDA, RDH. Bisphosphonates. Journal of the American Dental Association in August
2006.
•Howard C Tenenbaum et al .Bisphosphonates and periodontics : potential applications for regulation
of bone mass in the periodontium and other therapeutic/ diagnostic uses. JOP 2002;73:813-822.
•R. G. G. Russell, N. B. Watts, F. H. Ebetino, M. J. Rogers. Mechanisms of action of
bisphosphonates: similarities and differences and their potential influence on clinical efficacy.
Osteoporos Int (2008) 19:733–759.
•American Association of Oral and Maxillofacial Surgeons. Position Paper on Bisphosphonate-
Related Osteonecrosis of the Jaw—2009 Update.